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Clinical Implications of HCV Resistance
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DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
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Faculty
Program Director
Stefan Zeuzem, MDProfessor of Medicine Chief, Department of Medicine I
JW Goethe University Hospital Frankfurt, Germany
Faculty
Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Mary, University of LondonLondon, United Kingdom
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Faculty Disclosures
Stefan Zeuzem, MD, has disclosed that he has received fees for non-CME services from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche and consulting fees from Abbott, Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, iTherX, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, and Vertex.
Graham R. Foster, FRCP, PhD, has disclosed that he has received research support from Boeringher Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Novartis, and Roche and has served as a consultant and received fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche.
Introduction
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Introduction
PegIFN and RBV was standard-of-care therapy for chronic HCV for several yrs
Treatment difficult to tolerate, but forgiving
– Missing or delaying an occasional tablet rarely leads to treatment failure
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Cumulative RBV Exposure and SVR: Genotype 1 Treatment Completers
PegIFN alfa-2a 180 g/wk + RBV 1000/1200 mg/day100
0
20
40
60
80
> 97 > 80-97 > 60-80 0-60
SVRRelapse
P = .0006 for trend
Cochrane-Armitage test between RBV cumulative dose and SVR
5762
33
67
32
22
54
19
Cumulative RBV Exposure Levels (%)
Res
po
nse
(%
)
Reddy KR, et al. Clin Gastroenterol Hepatol. 2007;5:124-129.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Introduction
Direct-acting antivirals are less forgiving
– Boceprevir and telaprevir tablets should be taken every 8 hrs with careful attention to timing and food requirements
Suboptimal therapy may lead to drug resistance
Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.
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Drug Resistance Frequent in Patients Failing Boceprevir or Telaprevir TVR treatment-emergent resistance substitutions in
majority of isolates from subjects in phase III studies who did not achieve SVR[1]
Among BOC-treated subjects who did not achieve SVR in phase III studies and for whom samples were analyzed, 53% had ≥ 1 treatment-emergent NS3 protease amino acid substitutions[2]
Nearly all of these substitutions have been shown to reduce TVR or BOC anti-HCV activity in cell culture or biochemical assays[1,2]
1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011.
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Futility Rules for Boceprevir or Telaprevir + PegIFN/RBV
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [package insert]. May 2011.
Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of ~ 10-15 IU/mL.
Boceprevir[1,2] .
Time Point Criteria Action
Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue all therapy
Telaprevir[2,3] .
Time Point Criteria Action
Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue pegIFN/RBV
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Stopping Rules—The Theory
Courtesy of Christoph Sarrazin, MD.
Quasispecies with dominantwild-type virus and
single resistant variants
After ~ 4-24 wks,wild-type virus is
eliminated
PegIFN/RBV
PI + PegIFN/RBV
Baseline
Triple therapywith HCV PI
Wild typeMedium resistance/more fit
High resistance/unfitResistance with increased fitness
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Stopping Rules—The Facts: Multiple Mutations May Be More Troublesome Loss of detectable resistance in patients with resistant variant(s) at failure of TVR +
pegIFN/RBV (analysis includes only patients with follow-up data)
V36M Alone* R155K Alone† V36M + R155K
% of 1a failures (WT: 16%) 10 20 46
Median mos to loss (95% CI) 6 (4-9) 10 (9-13) 13 (10-13)
Pro
bab
ilit
y
Mos After Treatment Failure
R155K alone (n = 41)
R155K alone (n = 41)
V36M alone (n = 22)
V36M alone (n = 22)
V36M + R155K (n = 124)V36M + R155K (n = 124)
0.2
0.4
0.6
0.8
1.0
00 2 4 6 8 10 12 14 16 18
Sullivan J, et al. EASL 2011. Abstract 8.
*Comparison of V36M vs V36M + R155K: P < .0001. †Comparison of R155K vs V36M + R155K: P = .48.
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Loss of Detectable Resistance in Patients Stopping BOC + PegIFN/RBV Analysis includes only pts with follow-up data and resistant
variant(s) at failure
HCV-Resistant Variant Patients No Longer Harboring Resistant Variant at Long-term Follow-up (6-14 Mos), %
T54A 94
A156S 88
V55A 86
V36M 75
R155K 68
T54S 68
Barnard RJ, et al. AASLD 2011. Abstract 164.
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Resistance Profile of Approved and Investigational PIs
*Mutations associated with resistance in vitro only.
Halfon P, et al. J Hepatol. 2011;55:192-206.
Resistance mutations of NS3 PIs with a ≥ and < 4-fold increase in EC50 shown in red and white, respectively.
V36A/M T54A V55A Q80R/K R155K/T/Q A156S A156V/T D168A/V/T/H V170A
Telaprevir (linear) * *
Boceprevir (linear) *
SCH900518 (linear)
BILN-2061 (macrocyclic)
ITMN191 (macrocyclic) * *
MK7009 (macrocyclic) *
TMC435350 (macrocyclic)
BI-201335 (linear)
MK5172 (macrocyclic)
GS-9256 (macrocyclic)
ABT 450 (macrocyclic)
BMS-791325 (macrocyclic)
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Section 1 Take-Home Points
Stopping rules detailed in prescribing information should be strictly adhered to
Current understanding of PI failure patients
– Optimal regimen for retreatment is not yet clear
– However, retreatment with current PIs is not recommended
– Resistance mutations detected following failure typically decline in frequency following treatment discontinuation until wild-type variants once again predominate
– May take many mos
– Value of resistance testing at failure not yet clear
In this rapidly moving field, new approaches are currently being developed and assessed in clinical trials
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Recommendations for Missed PI Doses
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.
Timing of Missed Dose Action
Boceprevir[1]
< 2 hrs before next dose due Skip missed dose and resume regular dosing schedule
≥ 2 hrs before next dose due Take dose immediately and resume regular dosing schedule
Telaprevir[2]
> 4 hrs since dose usually taken Skip missed dose and resume regular dosing schedule
< 4 hrs since dose usually taken Take dose immediately and resume regular dosing schedule
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Minimal Viral Decline With PegIFN Alone, Enhanced With Addition of TVR
Resistance mutations emerged in TVR monotherapy arm within 4-7 days; subsequently suppressed by pegIFN/RBV
Kieffer TL, et al. Hepatology. 2007;46:631-639.
1Sequence analysis
-6
-5
-4
-3
-2
-1
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14Days
Ch
ang
e in
HC
V R
NA
Fro
m
Bas
elin
e (l
og
10 I
U/m
L)
TVR + PegIFN
(n = 8)
TVR (n = 8)
PegIFN + placebo (n = 4)
15
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
RBV Also Required in PI Combination Regimens
PROVE-2[1]
SV
R (
%)
0
20
40
60
80
100
48-wk BOC +PegIFN +
Full-Dose RBV(n = 16)
48-wk BOC + PegIFN +
Low-Dose RBV(n = 59)
SPRINT-1[2]
12-wk TVR + PegIFN + RBV
(n = 82)
12-wk TVR + PegIFN (no RBV)(n = 78)
SV
R (
%)
0
20
40
60
80
100
60
36
50
36
1. Hezode C, et al. N Engl J Med. 2009;360:1839-1850. 2. Kwo PY, et al. Lancet. 2010;376:705-716.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Improved Virologic Response When RBV ± PegIFN Added to GS-9256 + Tegobuvir GS-9256: NS3 protease inhibitor
Tegobuvir: nonnucleoside polymerase inhibitor
Zeuzem S, et al. Hepatology. 2012;55:749-758.
HCV RNA Response GS-9256 + Tegobuvir
(n = 15)
GS-9256 +Tegobuvir + RBV
(n = 13)
GS-9256 + Tegobuvir + PegIFN/RBV
(n = 14)
Median maximal change from baseline, log10 IU/mL
-4.1 -5.1 -5.7
Day 14 HCV RNA < 25 IU/mL, %
7 46 71
Day 28 HCV RNA < 25 IU/mL (RVR), %
7 38 100
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Section 2 Take-Home Points
Guidance is available in package inserts for management of missed doses
Both pegIFN and RBV required in current PI-based combination regimens
Patients should be counseled on the importance of adherence to all components of the treatment regimen
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Progression of Fibrosis in Rebiopsied Patients 282 patients with Ishak stage 0 or 1 on initial biopsy rebiopsied[1]
– Progression of fibrosis occurred in 42% of pts over median of 52.5 mos
Factors associated with fibrosis progression of ≥ 2 Ishak stages: age at first biopsy (P = .001) and median ALT level (P = .007)[1]
Fibrosis progression more rapid in patients coinfected with HIV[2]
1. Williams MJ, et al. J Viral Hepat. 2011;18:17-22. 2. Deng LP, et al. World J Gastroenterol. 2009;15:996-1003.
-1Change in Fibrosis Score0 1 2 3 4 5
0
10
Pat
ien
ts (
%)
20
30
40
50
60
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
100
0
60
SV
R (
%)
80
40
REALIZE: SVR in Previous Relapsers, Partial Responders, Null Responders
Previous Relapsers Previous Partial Responders
n/N=
Previous Null Responders
*P < .001 vs PR48.
20121/145
124/141
83*88*
16/68
24
29/49 26/48
59*54*
4/27
15
21/72 25/75
29*33*
2/37
5
T12/PR48PR48 LI T12/PR48
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
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PROVIDE: BOC-Based Therapy in Previous Null Responders Limited data on efficacy of BOC
in previous null responders because excluded from RESPOND-2 trial
Current study: single-arm, multicenter rollover study of pts from pegIFN/RBV arms of phase II/III BOC studies
– Current analysis of null responders from RESPOND-2 and SPRINT-2: < 2 log decline in HCV RNA after 12 wks of pegIFN/RBV (N = 52)
– Pts received 4-wk pegIFN/RBV lead-in followed by ≤ 44 wks triple therapy
Bronowicki JP, et al. EASL 2012. Abstract 11.
*2 patients are still receiving treatment. †Includes 3 patients who discontinued treatment during lead-in phase.
Responses in Previous Null Responders*
100
80
60
40
20
0
38
14
3/2219/50
SVR† Relapse
Pat
ien
ts (
%)
n/N =
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
SVR by Week-4 Response in Lead-in Arms of Treatment-Experienced Trials
1. Vierling JM, et al. EASL 2011. Abstract 481 2. Foster G, et al. EASL 2011. Abstract 6.
≥ 1 log decline< 1 log decline
0
20
40
60
80
100
SV
R (
%)
33
REALIZE (TVR)[2]
82
158
*Pooled data from RGT and arm 3.
0
20
40
60
80
100
SV
R (
%)
33
RESPOND-2* (BOC)[1]
76
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
SVR by Response at Wk 4 in Lead-in Arm With Boceprevir and Telaprevir
1. Foster G, et al. EASL 2011. Abstract 6. 2. Bronowicki JP, et al. EASL 2012. Abstract 11.
Partial NRRelapsers Null NR
N/A
56†64
72
36
55
0
20
40
60
80
100
SV
R (
%)
< 1 log ≥ 1 log
PROVIDE (BOC)*[2]
n/N = 14/22 13/36 5/9 36/50 6/11
*Excludes 4 pts who dropped out during lead-in phase and 8 who were direct enrollers (ie no pegIFN/RBV lead-in).†Majority of prior relapsers still receiving treatment.
REALIZE (TVR)[1]
62
94
56 59
15
54
0
20
40
60
80
100
SV
R (
%)
< 1 log ≥ 1 log
8/13 10/18106/113 16/2715/286/41
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
BMS-790052 + BMS-650032 ± PegIFN/RBV for 24 Wks in GT1 Null Responders Combinations of 2 DAAs + pegIFN ± RBV being evaluated for null responders
First published study combines NS5A inhibitor BMS-790052 with NS3 PI BMS-650032
In dual therapy arm, 2/2 GT1b vs 2/9 GT1a pts reached SVR12 and SVR24
– 6 GT1a pts had breakthrough and resistance to both agents
No viral breakthrough with quadruple therapy
BMS-790052 and BMS-650032 alone or + pegIFN/RBV generally well tolerated
Lok AS, et al. N Engl J Med. 2012;366:216-224.
Undetectable HCV RNA, % (n)
BMS-790052 + BMS-650032(n = 11)
BMS-790052 + BMS-650032 + PR(n = 10)
RVR 64 (7) 60 (6)
SVR12 36 (4) 100 (10)
SVR24 36 (4) 90 (9)*
*1 pt had detectable but not quantifiable HCV RNA levels at Wk 24 after treatment and undetectable HCV RNA levels on retesting 35 days later.
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Section 3 Take-Home Points
Assessing fibrosis score in previous null responders helpful to determine if treatment should be initiated immediately or if patient can wait for future options
~ 35% of null responders receiving BOC- or TVR-based regimens achieve SVR
Response to lead-in period may be helpful in previous null responders to identify patients who are IFN responsive
– IFN-nonresponsive patients more likely to fail therapy and develop resistance
New therapies may provide opportunity for higher SVR rates in previous null responders
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Reasons to Consider Immediate Treatment
Response rates more favorable in patients with milder vs more advanced disease[1,2]
Chronic HCV infection may impair quality of life[3]
New regimens in development might develop unexpected problems
– Some promising drugs fail in phase III clinical trials due to unexpected adverse effects
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364: 2405-2416. 3. Foster GR. J Hepatol. 1999;31(suppl 1):250-254.
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SVR by Fibrosis/Cirrhosis Stage in Patients Receiving BOC + PegIFN/RBV
Subgroup Analysis of SPRINT-2[1]
PR48BOC RGTBOC/PR48
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
F3/4
100
80
60
40
20
0
SV
R (
%)
F0/1/2
38
67
213/319
n/N =
38
9/24
52
22/42
41
14/34
211/313
67
F3/4
100
80
60
40
20
0
SV
R (
%)
F0/1/2
23
66
77/117
132/15
68
21/31
44
14/32
81/119
68
Subgroup Analysis of RESPOND-2[2]
123/328
n/N =
14/61
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PR48T12PRT8PR
SVR by Fibrosis/Cirrhosis Stage in Patients Receiving TVR + PegIFN/RBV
78
62
73
5347
33
0
20
40
60
80
100
No, Minimal, or Portal Fibrosis
Bridging Fibrosis or Cirrhosis
SV
R (
%)
134/288
n/N =
226/290
205/279
24/73
45/73
45/85
Subgroup Analysis of ADVANCE
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Reasons to Consider Deferring Therapy
Disease progression slow in many patients
Current regimens are complex with many adverse effects
If patient is hesitant to begin therapy, may be less adherent
– Could lead to outgrowth of resistant variants
New experimental therapies are being developed and may offer similar or better response rates with fewer adverse effects
– IFN-free regimens an active focus of research
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Current Standard-of-Care Therapy Is Complex Adherence to pegIFN/RBV
therapy decreases over time Triple therapy has greatly
increased treatment complexity, involves multiple daily pills plus injection drug
– BOC TID: 12 pills/day
– TVR TID: 6 pills/day
– RBV BID: 4-6 pills/day
– PegIFN: QW injection
Increased risks with nonadherence to triple therapy include potential for resistance
Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
Treatment Wk
(N = 5706)
100
80
60
40
20
0PegIFN RBV
1000-1213-2425-3637-48
959589
9786 84
76
Mea
n A
dh
eren
ce (
%)
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Several Drugs in Development Are Dosed Once or Twice Daily
*With ritonavir boosting.
QD
ABT-072
ABT-267
ABT 450*
ACH-1625
BI 201335
Daclatasvir
GS 5885
GS 9451
IDX 184
INX-189
MK-5172
Narlaprevir*
PSI-7977
PSI-938
TMC435
BID
ABT-333
Asunaprevir
BI 201335
BI 207127
BMS 791325
Danoprevir*
Filibuvir
GS9256
Mericitabine
Setrobuvir
Tegobuvir
Vaniprevir
VX-222
TID
BI 207127
Danoprevir
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Section 4 Take-Home Points
Treatment-naive patients with minimal fibrosis have the best chance for successful therapy
However, these patients can also afford to wait for future regimens
Therefore, if patient is hesitant about initiating therapy, could consider waiting for future options and explaining to patient
– Future therapies may have better response rates
– Future regimens may be less complex
Adherence to current regimens critical and if patient is hesitant about starting, may be better to defer therapy rather than risk development of resistant variants through poor adherence
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Conclusions
Resistance does occur with the new PI-based antiviral regimens
Careful adherence to the prescribing information may reduce the incidence of resistance
Impact of resistance development on response to future regimens not yet clear
Patients should be counseled about current and future possibilities and informed about the great uncertainties
Go Online for Additional Educational Programs on
HCV ResistanceInteractive Virtual Presentation providing expert opinion on how to avoid the development of HCV resistance with new direct-acting antiviral regimens through review of 4 patient cases
Expert Dialogue Module of key data and case scenarios on HCV resistance
3 Expert Viewpoints authored by expert faculty to enhance your knowledge of resistance in HCV
clinicaloptions.com/HCVResistance
April 18-22, 2012Barcelona, Spain
Highlights From Barcelona 2012CCO Independent Conference Coverage of the 47th Annual Meeting of the European Association for the Study of the Liver*
This program is supported by an educational grant from
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by educational grants from
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
April 18-22, 2012Barcelona, Spain
Highlights From Barcelona 2012CCO Independent Conference Coverage of the 47th Annual Meeting of the European Association for the Study of the Liver*
This program is supported by an educational grant from
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by educational grants from
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Faculty
Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Mary, University of LondonLondon, United Kingdom
David R. Nelson, MDProfessor of MedicineAssociate Dean for Clinical ResearchUniversity of Florida College of MedicineGainesville, Florida
Stefan Zeuzem, MDProfessor of MedicineChief, Department of Medicine IJ W Goethe University HospitalFrankfurt, Germany
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Faculty Disclosures
Graham R. Foster, FRCP, PhD, has disclosed that he has received consulting fees and fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, Roche, and Transgene.
David R. Nelson, MD, has disclosed that he has contracted research with Abbott, Bristol-Myers Squibb, Genentech, Gilead Sciences, Janssen, Merck, and Vertex.
Stefan Zeuzem, MD, has disclosed that he has received consulting fees from Abbott, Achillion, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, Roche, Santaris, and Vertex and has received fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Roche.
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Optimizing HCV Management With Current Therapies
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Retrospective Analysis of TVR Ph III Trials Underscores Validity of TVR Futility Rules No pt with HCV RNA > 1000 IU/mL
at Wk 4 (n = 25) or Wk 12 (n = 12) had SVR
Viral kinetics analysis of pts with HCV RNA > 1000 IU/mL at Wk 4
– 23 of 25 reached HCV RNA nadir before Wk 4
– In most pts, HCV RNA already increasing from nadir by Wk 4
Emergence of highly TVR-resistant variants in majority of pts with HCV RNA > 1000 IU/mL at Wk 4
Jacobson I, et al. EASL 2012. Abstract 55.
HCV NS3/4A Variant
Level of TVRResistance
Tx-Naive Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 14)
Tx-Exp’d Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 11)
V36M + R155K High 12* 8
A156S/T/V High 1 0
R155K Low 0 2
Wild type None 1 1
*1 patient had R155K present at baseline.
Tx Experienced (n = 11)Tx Naive (n = 14)
Wks on Treatment0 2 4 6 8 10 12
10
102
103
104
105
106
107
108
0 2 4 6 8 10 1210
102
103
104
105
106
107
108
HC
V R
NA
, IU
/mL
Wks on Treatment
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PROVIDE: Efficacy of BOC-Based Therapy in Treatment-Experienced Patients Limited data on efficacy of BOC in
previous null responders because excluded from RESPOND-2 trial
Current study: single-arm, multicenter rollover study of well characterized pts from pegIFN/RBV arms of phase II/III BOC studies
– Current analysis included null responders from RESPOND-2 and SPRINT-2: < 2 log decline in HCV RNA after 12 wks of pegIFN/RBV (N = 52)
– Pts received 4-wk pegIFN/RBV lead-in followed by ≤ 44 wks triple therapy
Bronowicki J, et al. EASL 2012. Abstract 11.
SVR According to Previous Treatment Category*100
80
60
40
20
0
40 (19/47)
68 (53/78)
56 (5/9)
Null Partial Relapse
Pat
ien
ts (
%)
*Does not include 4 patients dropping out during lead-in. Adjusted numbers if these patients were included are 38% (19/50) for previous null responders and 50% (5/10) for previous relapsers.
Previous Response
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Boceprevir + PegIFN/RBV in GT1 HCV Therapy–Naive HIV/HCV Coinfection
Mallolas J, et al. EASL 2012. Abstract 50.
BOC 800 mg TID + PegIFN/RBV*
(n = 64)
Placebo† + PegIFN/RBV*(n = 34)
HIV/genotype 1 HCV–coinfected patients naive to HCV treatment,
receiving effective antiretroviral
therapy
(N = 98)
*PegIFN 1.5 µg/kg/wk; RBV 600-1400 mg/day, according to weight, in divided BID dose.†Patients in placebo arm with HCV RNA ≥ lower limit of quantification at Wk 24 eligible to receive open-label BOC plus pegIFN/RBV.
PegIFN/RBV*lead-in(n = 64)
PegIFN/RBV*lead-in(n = 34)
Randomized 2:1; stratified by cirrhosis/fibrosis and HCV RNA
(< vs ≥ 800,000 IU/mL) Wk 4 Wk 48 Wk 72
Follow-up
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Higher SVR12 Rates With BOC + P/R vs P/R Alone in HIV/HCV Coinfection Interim efficacy analysis
– 3 BOC pts had not yet reached SVR12 time point
HIV-1 RNA breakthrough observed in 7 pts
– BOC + P/R: n = 3/64
– Placebo + P/R: n = 4/34
Tolerability similar to that seen in HCV monoinfection
– Similar rates of total and serious adverse events in BOC and placebo groups
– Higher rates of discontinuation due to toxicity with BOC (20%) vs placebo (9%)
Caution needed with drug-drug interactions
0
20
40
60
80
100
SV
R12
(%
)
P/R
n/N = 9/34
26.5
37/61
60.7*
BOC + P/R
*Reflects presented data; speaker noted verbally that remaining 3 pts have now reached and achieved SVR12
Mallolas J, et al. EASL 2012. Abstract 50.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Management of Anemia With BOC-Based HCV Therapy: EPO vs RBV Reduction Nested study within randomized trial of GT1 HCV therapy-naive pts receiving 4 wks
lead-in, then either 44 wks triple therapy or response-guided therapy (24-44 wks)
– Baseline Hb requirements: 12-15 g/dL for women, 13-15 g/dL for men
Secondary anemia management with RBV dose reduction, erythropoietin administration, or transfusion, allowed if Hb ≤ 8.5 g/dL
Patients discontinued if Hb ≤ 7.5 g/dL
Poordad F, et al. EASL 2012. Abstract 1419.
Pts with Hb 10 g/dL* during BOC-based
therapy(N = 500) Erythropoietin 40,000 IU/wk
(n = 251)
RBV Dose Reduction (by 200-400 mg/day)†
(n = 249)
*Patients could also be randomly assigned if Hb < 11 g/dL and predicted to be ≤ 10 g/dL before next protocol-specified visit. †Assessment at 2 wks. Second, third level of dose reduction (each by 200 mg/day) allowed, if required.
Stratified by black vs nonblack, anemia onset ≤ 16 wks vs > 16 wks
from initiation of lead-in
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
RBV Dose Reduction for First-line Anemia Management Did Not Impact SVR
82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia intervention
Similar SVR rates with 2 strategies, regardless of baseline characteristics
Poordad F, et al. EASL 2012. Abstract 1419.
Subgroup, % RBV Dose Reduction(n = 249)
EPO(n = 251)
Sex
Female 69 72 Male 77 69
Race
Black 53 49 Nonblack 75 76
Weight
< 75 kg 72 70 ≥ 75 kg 71 72
IL28B
TT 65 65 CT 70 67 CC 78 82
Fibrosis score
F0/1/2 74 72 F3/4 58 67
0
20
40
80
100
SV
R (
%)
RBV DR EPO
∆ -0.7% (95% CI: -8.6 to 7.2)*
71 71
178/249 178/251n/N =
*Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.
60
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
No Association Between Degree of Hb Decline and SVR in Pts Developing Anemia
Poordad F, et al. EASL 2012. Abstract 1419.
n/N =0
20
40
80
100
SV
R (
%)
Maximum Hb Decline (g/dL)
60
7/11 20/29 30/49 49/72 65/89 53/74 76/100 56/76
6469
6168
73 72 76 74
≤ 3 > 3 - ≤ 4 > 4 - ≤ 5 > 5
RBV DR EPO
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
CUPIC: Interim Analysis of Telaprevir and Boceprevir Use in Cirrhotics CUPIC: French compassionate use program designed to provide early access to TVR
and BOC after completion of phase III trials but before marketing authorization
– Patients enrolled at 55 sites beginning February 2011
– Genotype 1 HCV, compensated cirrhosis (Child-Pugh A), previous relapse or partial response to pegIFN/RBV
– 15% to 16% of patients included had esophageal varices; represents a group that did not qualify for inclusion in phase III trials
Interim analysis of patients who received 16 wks of one of the following regimens
– TVR-based therapy: TVR 750 mg TID + pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day for 12 wks followed by pegIFN/RBV for 36 wks
– Total TVR-based therapy: 140 days; median duration at current analysis: 84 days
– BOC-based therapy: 4-wk pegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day lead-in phase followed by BOC 800 mg TID + pegIFN/RBV for 44 wks
– Total BOC-based therapy: 168 days; median duration at current analysis: 140 days
Hezode C, et al. EASL 2012. Abstract 8.
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CUPIC: Efficacy of Telaprevir in Cirrhotics
~ 80% of patients treated with TVR-based therapy had undetectable HCV RNA at end of 12 wks of triple therapy
Hezode C, et al. EASL 2012. Abstract 8.
0
20
40
80
100
Un
det
ecta
ble
HC
V R
NA
(%
)
60
145/276
53
Wk 4 Wk 8 Wk 12 Wk 16
145/285
224/265
224/282
219/254
219/281
177/205
177/251
51
8579
8678
86
71
Per protocolITT
n/N =
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
CUPIC: Safety of Telaprevir in Cirrhotics
Hezode C, et al. EASL 2012. Abstract 8.
Safety Outcome, % Telaprevir-Based Therapy (n = 296)
Serious adverse events 48.6
Premature treatment discontinuation 26.0
Resulting from serious adverse events 14.5
Death 2.0 (sepsis [n = 2], pneumopathy [n = 1], bleeding of esophageal varices [n = 1], encephalopathy [n = 1], and lung carcinoma [n = 1])
Grade 3/4 nonhematologic adverse events
Infection 8.8
Rash 7.5
Hepatic decompensation 4.4
Hematologic adverse events and support
Anemia
• Grade 2 19.6
• Grade 3/4 10.1
• Use of erythropoietin 56.8
• Blood transfusion 15.2
Thrombocytopenia
• Grade 3/4 13.1
• Use of thrombopoietin 1.7
Neutropenia
• Grade 3/4 4.7
• Use of G-CSF 2.4
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
CUPIC: Efficacy of Boceprevir in Cirrhotics ~ 60% of patients treated with boceprevir-based therapy had
undetectable HCV RNA at Wk 16 of ongoing therapy
Hezode C, et al. EASL 2012. Abstract 8.
0
20
40
80
100
60
2/155
1
Wk 4 Wk 8 Wk 12 Wk 16
2/155
55/149
55/150
88/144
88/151
89/126
89/146
1
37 37
61 58
71
61
Per protocolITT
Un
det
ecta
ble
HC
V R
NA
(%
)
n/N =
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
CUPIC: Safety of Boceprevir in Cirrhotics
Hezode C, et al. EASL 2012. Abstract 8.
Safety Outcome, % Boceprevir-Based Therapy (n = 159)
Serious adverse events 38.4
Premature treatment discontinuation 23.9 Resulting from serious adverse events 7.4
Death 1.3 (bronchopulmonary infection [n = 1] and sepsis [n = 1])
Grade 3/4 nonhematologic adverse events
Infection 2.5 Rash 0 Hepatic decompensation 4.4
Hematologic adverse events and support
Anemia
• Grade 2 22.6
• Grade 3/4 10.1
• Use of erythropoietin 66.0
• Blood transfusion 10.7 Thrombocytopenia
• Grade 3/4 6.9
• Use of thrombopoietin 1.9 Neutropenia
• Grade 3/4 5.0
• Use of G-CSF 3.8
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
HCV PI Therapy for HCV Recurrence Following Liver Transplantation Multicenter experience
– Active, chronic GT1 HCV infection
– HCV recurrence: ≥ F2 (n = 20) or cholestatic hepatitis (n = 8)
In absence of trial data, pts treated off label with 1 of 3 regimens
– P/R lead-in for 4 wks, followed by BOC 800 mg TID + P/R (n = 17)
– TVR with lead-in (n = 5)
– P/R lead-in for 4 wks, followed by TVR 750 mg TID + P/R
– TVR without lead-in (n = 6)
– TVR 750 mg TID + P/R
Coilly A, et al. EASL 2012. Abstract 47.
P = .01
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
HCV PI Therapy for HCV Recurrence Following Liver Transplantation
Anemia was very frequent AE
– 71% with BOC; 55% with TVR
– > 90% of pts required EPO
1 death in TVR group
Calcineurin inhibitor dose reductions required
– BOC group
– Cyclosporine dose ↓ 1.3-fold
– Tacrolimus dose ↓ 5.0-fold
– TVR group
– Cyclosporine dose ↓ 4-fold
– Tacrolimus dose ↓ 35-fold
Wk 4
36 35
0
20
40
60
80
100
n = 11 n = 17
Co
mp
lete
RV
R (
%)
100Wk 8
56
70
n = 10 n = 160
20
40
60
80
Co
mp
lete
Vir
olo
gic
R
esp
on
se (
%)
Coilly A, et al. EASL 2012. Abstract 47.
TelaprevirBoceprevir
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Investigational IFN-Containing HCV Treatment Regimens
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Investigational Agents for HCV Discussed in This SlidesetClass Drugs
Interferons Peginterferon lambda-1a
Cyclophilin inhibitor Alisporivir
Nucleos(t)ide analogue polymerase inhibitor GS-7977Mericitabine
Nonnucleoside polymerase inhibitor ABT-072ABT-333BI 207127 Tegobuvir
Protease inhibitor ABT-450AsunaprevirBI 201335 DanoprevirGS-9451Simeprevir (TMC435)
NS5A inhibitor DaclatasvirGS-5885
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
EMERGE: PegIFN lambda-1a vs PegIFN alfa-2a in GT 2/3 HCV Treatment-Naive Pts Interim analysis of randomized, blinded, active-controlled phase IIb trial
Zeuzem S, et al. EASL 2012. Abstract 10.
Treatment-naive patients infected with
genotype 2/3 HCV(N = 118)
PegIFN lambda-1a 120 µg/wk + RBV†
(n = 29)
PegIFN lambda-1a 180 µg/wk + RBV† (n = 29)
PegIFN lambda-1a 240 µg/wk + RBV† (n = 30)
Wk 24Genotyping at baseline
*All patient numbers pertain only to patients with GT2/3 HCV. Study also included GT1/4 patients, but current analysis limited to GT2/3 HCV.†RBV dosed at 800 mg/day for GT2/3 patients.
PegIFN alfa-2a 180 µg/wk + RBV† (n = 30)
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SVR rates comparable in pegIFN lambda-1a arms vs pegIFN alfa-2a
PegIFN lambda-1a 180 μg dosage chosen for phase III trials
EMERGE: Efficacy and Safety Outcomes
Fewer hematologic AEs and ALT/AST elevations with pegIFN lambda-1
– No difference in other AE categories
Zeuzem S, et al. EASL 2012. Abstract 10.
SV
R24
(%
)
0
40
60
80
100
65.5
20
75.9
60.053.3
N = 29 29 30 30
Lambda120 µg
Lambda180 µg
Lambda240 µg
Alfa180 µg
Adverse Event, %Lambda180 µg(N = 29)
Alfa180 µg(N = 30)
HB low: < 10 g/dL or ∆ > 3.4 g/dL
6.9 44.8
RBV dose reduction(Hb associated)
0 23.3
Neutrophils low: < 750/mm3 0 27.6
Platelets low:< 100,000/mm3 0 24.1
PegIFN dose reduction(hematologic abnormality)
0 23.3
ALT/AST > 5 to 10 x ULN 6.9 13.3
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
ATOMIC: GS-7977 + PegIFN/RBV in Treatment-Naive GT1 Patients Interim analysis of randomized, open-label phase II study
Kowdley K, et al. EASL 2012. Abstract 1.
Treatment-naive, noncirrhotic
patients chronically infected with HCV*
(N = 332)
GS-7977 400 mg QD +PegIFN/RBV
(n = 52)
GS-7977 400 mg QD + PegIFN/RBV(n = 125)
GS-7977 400 mg QD +PegIFN/RBV
(n = 155)
Wk 24Wk 12Randomized 1:2:3; stratified by
IL28B genotype (CC vs non-CC) and HCV RNA (≤ vs > 800,000 IU/mL)
GS-7977 400 mg QD(n = 75)
GS-7977 400 mg QD +RBV
(n = 75)*All infected with GT1 HCV, except for 16 patients with GT4 or 6 HCV who were eligible for enrollment in the 24-wk arm of GS-7977 plus pegIFN/RBV.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
ATOMIC: High Rate of SVR With 12 Wks of GS-7977 + PegIFN/RBV
Virologic relapse rare to date and not associated with primary resistance
– No S282T mutation observed in 4 patients with relapse assessed by population sequencing
GS-7977 generally well tolerated in combination with pegIFN/RBV
– No serious adverse events attributed to GS-7977
Kowdley K, et al. EASL 2012. Abstract 1.
Pat
ien
ts (
%)
0
40
60
80
100
20
7977 + P/R12 + 12 Wks
7977 + P/R12 Wks
7977 + P/R24 Wks
9498 94 9098 99
929799
92
Wk 4EOT
SVR4SVR12
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
ASPIRE: Simeprevir (TMC435) + P/R in Treatment-Experienced GT1 Patients Double-blind,
placebo-controlled phase IIb trial
Zeuzem S, et al. EASL 2012. Abstract 2.
Patients with chronic GT1 HCV who failed
previous pegIFN/RBV(16% to 20% in each group had F4 fibrosis)
(N = 462)
Wk 48Wk 12 Wk 24
TMC435 150 mg QD + P/R*(n = 68) Placebo + P/R*
24-wk
follow-up
TMC435 100 mg QD + P/R*(n = 66) Placebo + P/R*
TMC435 150 mg QD + P/R*(n = 66) Placebo + P/R*
TMC435 100 mg QD + P/R*(n = 65) Placebo + P/R*
TMC435 100 mg QD + P/R*(n = 66)
TMC435 150 mg QD + P/R*(n = 65)
Placebo + P/R*(n = 66)
*PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
ASPIRE: SVR24 Rates According to Previous Response Category
In TMC435 150-mg group, SVR24 rates similar in patients with/without baseline Q80K
– Among GT1a patients, SVR24 in 61% of those with Q80K and 66% of those without Q80K
Zeuzem S, et al. EASL 2012. Abstract 2. Lenz O, et al. EASL 2012. Abstract 9.
80
SV
R24
(%
)
0
40
60
100
20
Relapsers Partial Responders Null Responders
37
85 85
9
57
75
19
4651
27 79 79 23 68 69 16 50 51n =
No advantage of extending therapy beyond 12 weeks; dosing groups pooled in subsequent analysis
TMC435 100 mg* + PR48TMC435 150 mg* + PR48
Placebo + PR48
*Pooled.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
ASPIRE: Safety Analysis
Zeuzem S, et al. EASL 2012. Abstract 2.
Hematologic changes similar to placebo
TMC435 associated with mild, transient, asymptomatic increases in bilirubin
– Bilirubin elevations did not exceed ULN
– No significant difference in incidence between 100 mg and 150 mg doses
110
130
140
150
160
120
Wk
Me
an
± S
E o
f A
ctu
al
Va
lue
s
of
To
tal
Hb
(g
l/L
)
170
0 246 8 12 16 20 2428 36 42 48 52 72
Wks 1-12 TMC435 100 mgWks 12-24 TMC435 100 mgWks 24-48 TMC435 100 mg
Wks 1-12 TMC435 150 mgWks 12-24 TMC435 150 mgWks 24-48 TMC435 150 mg
Placebo PR48
LLN
Hb Neutrophil Count Bilirubin (Total)
LLN
ULN
0
1
2
3
4
Wk
Me
an
± S
E o
f A
ctu
al
Va
lue
s o
f N
eu
tro
ph
ils
Se
gm
en
ted
(g
iga
/L)
0 24 6 8 12 18 20 2428 36 42 48 52 72
0
10
15
20
5
Wk
Me
an
± S
E o
f A
ctu
al
Va
lue
s
of
To
tal
Bil
iru
bin
(μ
mo
l/L
)
0 246 8 12 18 20 2428 36 42 48 52 72
5 25
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Investigational All-Oral HCV Treatment Regimens
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
VITAL-1: Alisporivir-Based Therapy for Treatment-Naive GT2/3 Patients
Pawlotsky JM, et al. EASL 2012. Abstract 1405.
Treatment-naive patients with chronic GT2/3 HCV
infection (N = 340)
Alisporivir 1000 mg QD(n = 83)
Alisporivir 600 mg QD + RBV(n = 84)
Alisporivir 800 mg QD + RBV (n = 94)
Wk 24Stratified by HCV RNA and HCV genotype
Alisporivir 600 mg QD + PegIFN(n = 39)
PegIFN alfa-2a/RBV (n = 40)
All pts received alisporivir loading dose of 600 mg BID during first wk. PegIFN alfa-2a dosed 180 µg/wk. RBV dosed 800 mg/day.
Wk 4: RVR assessed Wk 6
24-wkF/U
Alisporivir 600 mg QD + PegIFN/RBV
Alisporivir 1000 mg QD
Alisporivir 600 mg QD + PegIFN/RBV
Alisporivir 600 mg QD + RBV
Alisporivir 600 mg QD + PegIFN/RBV
Alisporivir 800 mg QD + RBV 800 mg/day
Alisporivir 600 mg QD + PegIFN/RBV
Alisporivir 600 mg QD + PegIFN
RVR:
No RVR:
RVR:
No RVR:
RVR:
No RVR:
RVR:
No RVR:
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
VITAL-1: SVR12 by Per-Protocol Analysis
High SVR rates with alisporivir-based therapy, including IFN-free regimens
– However, development of alisporivir currently on hold due to several cases of pancreatitis (with 1 death) in ~ 1800 patients treated to date
Pawlotsky JM, et al. EASL 2012. Abstract 1405.
Overall SVR12 SVR12 in Pts Receiving IFN-Free Therapy
SV
R12
(%
)
0
40
60
80
100
20
ALV1000
81 83 8177
58
ALV600RBV
ALV800RBV
ALV600Peg
P/R0
40
60
80
100
20
ALV1000
8293 91
ALV600RBV
ALV800RBV
82 84 93 39 40n = 17 29 32n =
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Co-Pilot: 12-Wk ABT-450/r + ABT-333 + RBV in Tx-Naive and -Exp’d GT1 Patients Interim analysis of nonrandomized, prospective, open-label phase II trial
Poordad F, et al. EASL 2012. Abstract 1399.
Treatment-naive patients infected with
genotype 1 HCV(n = 33)
ABT-450/Ritonavir 250/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD
(n = 19)
ABT-450/Ritonavir 150/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD
(n = 14)
Wk 12
ABT-450/Ritonavir 150/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD
(n = 17)
48 wks of follow-up
Treatment-experienced* patients infected with
genotype 1 HCV(n = 17)
*Previous null response (< 2 log10 decrease in HCV RNA by Wk 12) or partial response (HCV RNA above limit of detection during treatment)
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Co-Pilot: Virologic Outcomes
SVR12 in 94% of treatment-naive and 47% of treatment-experienced patients
– Responses independent of IL28B genotype
Poordad F, et al. EASL 2012. Abstract 1399.
Pat
ien
ts (
%)
0
40
60
80
100
20
ABT-450/r 250/100 mg QD+ ABT-333 + RBVTreatment naive
(n = 19)
ABT-450/r 150/100 mg QD+ ABT-333 + RBVTreatment naive
(n = 14)
ABT-450/r 150/100 mg QD+ ABT-333 + RBV
Nonresponders(n = 17)
RVReRVRSVR4SVR12
90 90 95 95
79 79
93 93
77
5947 47
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Co-Pilot: Safety Outcomes
Laboratory Abnormalities of Interest, %
Tx Naive,ABT-450/r 250/100 mg
+ ABT-333 + RBV(n = 19)
Tx Naive, ABT-450/r 150/100 mg
+ ABT-333 + RBV (n = 14)
Tx Experienced,ABT-450/r 150/100 mg
+ ABT-333 + RBV (n = 17)
Total bilirubin ≥ 2 x ULN
15.8 21.40
Creatinine ≥ 1.5 ULN* 10.5 0 0
CrCl < 50 mL/min* 10.5 0 0
ALT ≥ 5 x ULN 5.3 0 0
Most notable laboratory abnormalities: increased bilirubin and creatinine
– Hyperbilirubinemia consistent with known effect of ABT-450 on OATP1B1 bilirubin transporter
– Both cases of increased creatinine resolved without ABT-450 or ABT-333 dose adjustment
Poordad F, et al. EASL 2012. Abstract 1399.
*Creatinine elevations and shortened creatinine clearance occurred in same 2 patients.
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
INFORM-SVR: Mericitabine + Danoprevir/r + RBV in Treatment-Naive GT1 Patients
Gane E, et al. EASL 2012. Abstract 1412.
Tx-naive patients
with chronic
GT1 HCV(N = 169)
Mericitabine 1000 mg BID +Danoprevir/Ritonavir
100/100 mg BID +Ribavirin 1000-1200 mg/day
Follow-up
Wk 12 Wk 24 Wk 36 Wk 48
eRVR2
Mericitabine 1000 mg BID +Danoprevir/Ritonavir
100/100 mg BID +Placebo
Mericitabine + Danoprevir/Ritonavir +
Ribavirin
Mericitabine + Danoprevir/Ritonavir +
Ribavirin
Mericitabine + Danoprevir/Ritonavir
Mericitabine + Danoprevir/Ritonavir
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
eRVR2
No eRVR2
Interim analysis of multicenter, randomized, double-blind, parallel-group phase IIb study
– Randomization to 12-wk RBV-containing arm and to entire RBV-free arm stopped prematurely because of high relapse rates
No eRVR2
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
INFORM-SVR: SVR12 Rates According to HCV Subtype and IL28B Genotype SVR12 rates higher for GT1b, IL28B non-CC patients
Gane E, et al. EASL 2012. Abstract 1412.
SV
R12
(%
)
0
40
60
80
100
20
Overall CC Non-CC
IL28B Genotype
n/N =
41
26
71
3227
5044
25
76
All (n = 64)GT1a (n = 43)GT1b (n = 21)
26/64 11/43 15/21 6/19 4/15 2/4 20/45 7/28 13/170
40
60
80
100
20
n/N =
SVR12 Rates in Patients Receiving 24 Wks MCB + DNV/r + RBV
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Daclatasvir + GS-7977
Daclatasvir + GS-7977 ± RBV in Tx-Naive GT1, 2/3 Pts
Sulkowski M, et al. EASL 2012. Abstract 1422.
Treatment-naive patients with
GT2 or 3 HCV infection
(n = 44)
Daclatasvir + GS-7977(n = 14)
Daclatasvir + GS-7977(n = 14)
Follow-up
Daclatasvir + GS-7977 + Ribavirin(n = 14)
Daclatasvir + GS-7977 + Ribavirin(n = 15)
Wk 1 Wk 24 Wk 48
GS-7977 dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 pts (1000 -1200 mg/day); 800 mg/day for GT 2/3 pts.
Treatment-naive patients with GT1a or 1b
HCV infection(n = 44)
Follow-up
GS-7977 (n = 15)
Daclatasvir + GS-7977GS-7977 (n = 16)
Follow-up
Follow-up
Follow-up
Follow-upA
B
C
D
E
F
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
Sulkowski M, et al. EASL 2012. Abstract 1422.
Pat
ien
ts (
%)
0
40
60
80
100
20
100 100 100
87 8693
100100 100
Genotype 1a/1b HCV
n =
Group AGroup BGroup C
Light:< LODDark: < LLOQ anddetectable
8793
73
87 8693
100 100 100
15 14 15 15 14 15 15 14 15
Wk 4 Wk 24 (EOT)
SVR4
mITT analysis, bars not reaching 100% after Wk 4 reflect missing values.
0
40
60
80
100
20
100100 10094
100
86
100
86†
Genotype 2/3 HCV
n =
Group DGroup EGroup F
Light:< LODDark: < LLOQ anddetectable
8879
64
93 9386 88
100
79
16 14 14 16 14 14 16 14 14
Wk 4 Wk 24 (EOT)
SVR4
mITT analysis, bars not reaching 100% after Wk 4 reflect missing values.*1 patient required addition of pegIFN-alfa/RBV (tx intensification), 1 patient with relapse at posttreatment Wk 4†2 patients lost to follow-up (following Wk 12 and 24 visits).
Pat
ien
ts (
%)
88*
Daclatasvir + GS-7977 ± RBV: Efficacy Analysis According to Genotype
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
SOUND-C2: BI 201335 + BI 207127 ± RBV in Tx-Naive GT1 Patients
Zeuzem S, et al. EASL 2012. Abstract 101.
Tx-naive patients with GT1
HCV (7% to 17% in each group had
cirrhosis)(N = 362)
BI 201335 120 mg QD + BI 207127 600 mg TID + RBV
(n = 81)
BI 201335 120 mg QD + BI 207127 600 mg TID + RBV
(n = 80)
BI 201335 120 mg QD + BI 207127 600 mg TID + RBV
(n = 77)
Wk 16
BI 201335 120 mg QD + BI 207127 600 mg BID + RBV
(n = 78)
BI 201335 120 mg QD + BI 207127 600 mg TID, no RBV
(n = 46)*
Stratified by HCV subtype and IL28B genotype
*Randomization to this arm stopped early due to FDA concerns regarding lack of RBV.
12-wk follow-upfor SVR12
Wk 28 Wk 40
Weight-based RBV dosing (1000-1200 mg/day).
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68
SOUND-C2: Efficacy According to Study Arm, HCV Subgenotype, and IL28B
Zeuzem S, et al. EASL 2012. Abstract 101.
SV
R12
(%
)
0
40
60
80
100
20
BID28 wks
RBV
TID28 wks
TID40 wks
RBV
TID28 wks
RBV
TID16 wks
RBV
32
71
38
71
42
62
32
82
53
0
1a non-CC All 1b and 1a-CC
SVR According to IL28B and HCV Subtype (ITT)
59
All patients
6156
39
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SOUND-C2: With BID Dosing, Higher SVR12 in Pts With GT1b or GT1a-IL28B CC
Zeuzem S, et al. EASL 2012. Abstract 101.
SV
R12
(%
)
n/N =
32
7584 82
1anon-CC
1aCC
1bnon-CC
1bCC
SVR According to IL28B and HCV Subtype:BID 28 Wks + RBV (ITT)
0
40
60
80
100
20
7/22 6/8 31/37 9/11
HCV Subtype and IL28B Genotype
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37 (10%) of 362 patients in SOUND-C2 had compensated cirrhosis
SVR12 rates higher for GT 1b pts; impact of IL28B could not be assessed due to small numbers
Favorable safety with BID dosing, higher rates of discontinuation and serious AEs with TID dosing
SOUND-C2 Subanalysis: Efficacy and Safety in Pts With Compensated Cirrhosis
Soriano V, et al. EASL 2012. Abstract 1420.
TID 16, 28, 40 wks*
RBV
SV
R (
%)
0
40
60
80
100
20
BID 28 wks
RBV
TID 28 wks
*SVR12 data not yet available for TID 40 wk arm, so SVR4 rates used in analysis.
43
3/7 9/14 2/6 5/7 0/0 1/3
64
33
71
33
GT1aGT1b
SVR12 According to HCV GT
n/N =
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Pilot: ABT-450/r + ABT-072 + RBV in Treatment-Naive GT1 HCV, IL28B CC Pts Single-arm, open-label, pilot study:
ABT-450/r 150/100 mg QD + ABT-072 400 mg QD + weight-based RBV 1000-1200 mg/day for 12 wks
100% of pts achieved primary endpoint of eRVR; 91% went on to SVR12 and SVR24
2 relapses posttherapy
– 1 at posttreatment Wk 12; resistance variant observed only in protease
– D168V variant observed in 36% of clones sequenced
– 1 late relapse at posttreatment Wk 36; resistance variant observed only in polymerase
– Y448H variant observed in 99% of clones sequenced
Lawitz E, et al. EASL 2012. Abstract 13.
RVR eRVR SVR12 SVR24
Pat
ien
ts (
%)
0
40
60
80
100
20
100 100
91 91
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4-Drug Therapy With GS-5885, GS-9451, Tegobuvir, and RBV in Tx-Naive GT1 HCV Interim analysis of randomized phase II study
Sulkowski M, et al. EASL 2012. Abstract 1421.
Tx-naive patients with chronic GT1
HCV infection(N = 140)
GS-5885 30 mg QD +GS-9451 200 mg QD + Tegobuvir 30 mg BID +
Ribavirin (n = 46)
Randomized 1:2; stratified by HCV RNA
(≤ vs > 800,000 IU/mL) and HCV 1 subtype (1a vs 1b)
*Patients with HCV RNA ≥ 25 IU/mL at Wk 2 offered rescue therapy including pegIFN or study discontinuation.†Patients rerandomized if HCV RNA < 25 IU/mL at Wks 2-10.
GS-5885 90 mg QD +GS-9451 200 mg QD + Tegobuvir 30 mg BID +
Ribavirin (n = 94)
Wk 2* Wk 12 Wk 24
GS-5885 90 mg QD +GS-9451 200 mg QD + Tegobuvir 30 mg BID +
Ribavirin
Follow-up
Rerandomized†
Follow-upfor SVR24
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All-Oral 4-Drug Therapy: Virologic Response and Virologic Breakthrough Four-drug regimen provided high rates of SVR12 in noncirrhotic
patients with GT1 HCV infection
– 81% with 12-wk therapy (n = 21)
– Interim analysis; data collection on 24-wk therapy ongoing
Virologic breakthrough, relapse rates lower in GT1b vs 1a infection
– Virologic breakthrough associated with emergence of multidrug resistance
Lower virologic breakthrough rates with IL28B CC vs non-CC genotype
Well tolerated over 24 wks of treatment
Sulkowski M, et al. EASL 2012. Abstract 1421.
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Daclatasvir + Asunaprevir in GT1b Pts With IFN Intolerance or Null Response 24 wks of daclatasvir 60 mg QD +
asunaprevir 200 mg BID (N = 43)
– 10 pts received asunaprevir 600 mg BID
Among pts with virologic breakthrough (7.0%) or relapse (9.3%), almost all had trough daclatasvir and asunaprevir plasma concentrations below median
Suzuki F, et al. EASL 2012. Abstract 14.
Wk 4RVR
Wk 12cEVR
End ofTreatment*
SVR12
HC
V R
NA
Un
de
tec
tab
le (
%)
0
40
60
80
100
20
*End of treatment = Wk 24 or last on-treatment visit for pts who discontinued early.ITT (missing = failure) analysis.
SVR24
Null responders (n = 21)
Ineligible/intolerant (n = 22)
52
86 91 91 91 91 91
6464
86
11/21
19/22
19/21
20/22
19/21
19/21
19/21
14/22
14/22
19/22
ASV and DCV Trough Plasma Concentrationsin Patients With SVR or Virologic Failure
800
600
400
200
100
100 200 400 600 800 1000
Daclatasvir Ctrough (ng/mL)
As
un
ap
rev
ir C
tro
ug
h (
ng
/mL
)Virologic failures
SVRRelapseBreakthrough
Note: Multiple determinationare shown for some patients.*Pharmacokinetic values from asingle patient with documentednoncompliance after sampling.
*
*
Median 57M
ed
ian
20
1
n/N =
clinicaloptions.com/hepatitisClinical Implications of HCV Resistance
*Stopped all therapy at Wk 12 if eRVR2 (HCV RNA < 15 IU/mL at Wks 2-10); continued to Wk 24 if no eRVR2.
DAUPHINE: Danoprevir/r + PegIFN/RBV in GT1/4 Treatment-Naive Patients Interim analysis of multicenter, randomized, open-label phase IIb study
Everson G, et al. EASL 2012. Abstract 1177.
Treatment-naive pts with GT1/4
HCV infection, F0-2 fibrosis, HCV RNA
≥ 50,000 IU/mL(N = 421)
Danoprevir/Ritonavir 200/100 mg q12h + P/R
(n = 94)
Danoprevir/Ritonavir 100/100 mg q12h + P/R
(n = 93)
Danoprevir/Ritonavir 50/100 mg q12h + P/R
(n = 94)
Wk 12 Wk 24 Wk 36
Danoprevir/r 100/100 mg q12h
+ P/R*(n = 94)
P/R (rollover offered to patients without cEVR)
DNV/r 100/100 mg q12h + P/R
Follow-upfor SVR24
Wk 48 Wk 60
DNV/r 200/100 mg q12h + P/R P/RRollover
==
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DAUPHINE: Preliminary SVR12 Rates in Pts Treated for 24 Wks With DNV/r + P/R SVR12 rates increased with higher doses of DNV/r
Everson G, et al. EASL 2012. Abstract 1177.
SV
R12
(IT
T),
(%
)
0
40
60
80
100
20
86
77
65
DNV/r 200 mg + P/RDNV/r 100 mg + P/RDNV/r 50 mg + P/R
79/92 72/93 61/94n/N =
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Hepatocellular Carcinoma
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Brivanib in Pts With Advanced HCC With Progression on or Intolerance to Sorafenib BRISK-PS: multinational, randomized, double-blind, placebo-controlled phase III trial
– Patients randomized to brivanib 800 mg QD (n = 263) or placebo (n = 132), each with supportive care
No improvement in OS in patients with advanced HCC who failed sorafenib
Llovet J, et al. EASL 2012. Abstract 1398.
Mos
Pro
ba
bil
ity
Ali
ve
0
0.4
0.6
0.8
1.0
0.2
Overall Survival
Brivanib Placebo183/263
9.4101/132
8.20.89 (0.69-1.15)
.3307
Events/patients, nMedian OS, mosHR (95.8% CI)*P (stratified log rank)
Pts at Risk, nBrivanibPlacebo
*95.8% CI adjusted for interim analysis
0
263132
2
239117
4
20894
6
16375
8
13464
10
9549
12
7735
14
5525
16
4019
18
3016
20
1711
22
127
24
54
26
23
28
02
30
00
Time to Progression
Mos
Pro
ba
bil
ity
of
Pro
gre
ss
ion
0
0.4
0.6
1.0
0.8
0.2
Brivanib Placebo151/263
4.275/132
2.70.56 (0.42-0.78)
.0001
Events/patients, nMedian TTP, mosHR (95% CI)P (log rank)
Pts at Risk, n BrivanibPlacebo
0
263132
2
14445
4
9221
6
376
8
205
10
92
12
31
14
21
16
11
18
01
22
01
24
00
20
01
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