new data on resistance to daas and implications for therapy.2015
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Nezam H. Afdhal, MD, FRCPIProfessor of MedicineHarvard Medical SchoolBeth Israel Deaconess Medical CenterBoston, Massachusetts
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
This activity is supported by an independent educational grant from Janssen Therapeutics.
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clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
Faculty
Program Chair
Nezam H. Afdhal, MD, FRCPIProfessor of Medicine Harvard Medical SchoolBeth Israel Deaconess Medical CenterBoston, Massachusetts
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
FacultyJordan J. Feld, MD, MPHAssociate Professor of Medicine University of TorontoHepatologistToronto Centre for Liver DiseaseSandra Rotman Centre for Global HealthToronto, Canada
Norah Terrault, MD, MPHProfessor of Medicine and Surgery Director, Viral Hepatitis CenterDivision of GastroenterologyUniversity of California, San FranciscoSan Francisco, California
Mark S. Sulkowski, MDProfessor of MedicineMedical Director, Viral Hepatitis CenterDivisions of Infectious Diseases and Gastroenterology/HepatologyJohns Hopkins University School of MedicineBaltimore, Maryland
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Faculty Disclosures
Nezam Afdhal, MD, FRCPI, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, and Vertex; has received consulting fees from AbbVie, Achillion, Catabasis, Cocrystal, Echosens, Gilead Sciences, GlaxoSmithKline, Janssen, Ligand, Merck, Roivant, Sandhill Scientific, and Spring Bank; and has stock options with Spring Bank.
Jordan J. Feld, MD, MPH, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Theravance and funds for research support from AbbVie, Boehringer Ingelheim, Gilead Sciences, Janssen, Merck, and Santaris.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
Faculty Disclosures
Mark S. Sulkowski, MD, has disclosed that he has received consulting fees from AbbVie, Achillion, Bristol‐Myers Squibb, Gilead Sciences, Janssen, and Merck; and funds for research support (paid to his institution) from AbbVie, Bristol‐Myers Squibb, Gilead Sciences, Janssen, and Merck.
Norah Terrault, MD, MPH, has disclosed that she has received funds for research support from AbbVie, Biotest, Eisai, Gilead Sciences, Novartis, and Vertex and consulting fees from Achillion, Biotest, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
Virologic Barriers to Resistance
Genetic barrierNumber and type of nucleotide changes required for a virus to acquire resistance to an antiviral regimen[1]
Viral fitnessRelative capacity of a viralvariant to replicate in a given environment
1. Rong L, et al. Sci Transl Med. 2010;2:30ra32. 2. Le Pogam S et al. J Virol. 2006;80:6146-6154. 3. Le Pogam S, et al. J Infect Dis. 2010;202:1510-1519
Fitness of Polymerase Inhibitor Mutants[2,3]
Wild
Typ
e
L419
M
M42
3T
I482
LL4
19M
/M42
3T
S282
T
1
.75
.5
.25
0
% F
itnes
s
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Resistant Variants Are Present Before and Can Be Selected During Treatment HCV is a mixture of related but distinct populations of virions in each pt[1]
Most resistant variants are unfit and may be undetectable prior to therapy[2,3]
1. Pawlotsky JM. Clin Liver Dis. 2003;7:45-66. 2. Kuntzen T, et al. Hepatology. 2008;48:1769-1778. 3. Bartels DJ, et al. J Infect Dis. 2008;198:800-807. Image reproduced and adapted with permission from Forum for Collaborative HIV Research. www.hivforum.org
Antiviral therapy eliminates sensitive variants Resistant variants expand
Sensitive virusResistant virus
Antiviral therapy
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HCV NS3/4A Protease Resistance
Lenz O, et al. Antimicrob Agents Chemother. 2010;54:1878-1887. Reproduced with permission from American Society for Microbiology. doi:10.1128/AAC.01452-09 Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Q80R155
D168
A156
F43
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Naive Exp’d 1a + Q80K
1a no Q80K
All pts
97
Impact of Treatment Exp, Q80K Depends on Cirrhosis (12 Wks’ SMV + SOF in GT1)
1. Kwo P, et al. EASL 2015. Abstract LP14. 2. Lawitz E, et al. EASL 2015. Abstract LP04.
SVR
12 (%
)
100
80
60
40
20
0
97 95 96
112/115
38/40
44/46
68/70n/N =
Naive Exp’d
Treatment History
HCV GT
1a + Q80K
1a no Q80K
97
150/155
All pts
8879
74
92
44/50
42/53
25/34
35/38
Treatment History
HCV GT
83
86/103
No Cirrhosis (OPTIMIST-1[1]) Cirrhosis (OPTIMIST-2[2])
100
80
60
40
20
0n/N =
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OPTIMIST-2: Resistance Analysis in GT1 Cirrhotics in Whom SMV + SOF Failed Treatment-emergent NS3 mutations detected in 79%
(11/14) of evaluable pts who did not achieve SVR12
– Observed at position 168, R155K, or combinations
NS5B polymorphism S282T not detected at baseline or at time of treatment failure
No NS3 baseline polymorphisms observed aside from Q80K
Lawitz E, et al. EASL 2015. Abstract LP04.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
AASLD/IDSA Guidance for Resistance Testing When Considering SMV + SOF In pts with both genotype 1a HCV infection and
compensated cirrhosis, if considering SMV + SOF, test for Q80K polymorphism
– If Q80K variant is present, consider a regimen other than SMV + SOF
Applies to treatment-naive and treatment-experienced pts
Q80K testing not required for:
– Pts with genotype 1b HCV infection
– Pts without cirrhosis
– Pts in whom you are considering other DAAsAASLD/IDSA/IAS-USA. HCV Guidance.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
ION-2: DAAs Effective Against NS3 RAVs After Boceprevir or Telaprevir
Virologic failure: 1 breakthrough in 24-wk LDV/SOF + RBV due to nonadherence; 11 relapses (7 in 12-wk LDV/SOF, 4 in 12-wk LDV/SOF + RBV)
14% of pts had NS5A RAVs at baseline; 89% of these achieved SVR12; 71% of pts had NS3 RAVs at baseline; 98% of these achieved SVR12
40/43
62/66
45/47
62/64
58/58
49/50
58/59
51/51
12 Wks 24 WksLDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
SVR
12 (%
)
100
80
60
40
20
0
93 94 96 97 1009898100
Failure of pegIFN/RBV
Failure of PI
Treatment History
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
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Fold-Change in EC50 Genotype 1a Genotype 1bPosition M28T Q30R L31M/V Y93H/N L31V Y93H/NFDA approvedDaclatasvir[1,3] > 100 x > 1000 x > 100 x > 1000 x < 10 x < 100 x
Ledipasvir[1] 20 x > 100 x > 100 x > 1000 x > 1000 x/?
Ombitasvir[2] > 1000 x > 100 x< 3 x
> 10,000 x < 10 x < 100 x> 100 x
1. Cheng G, et al. EASL 2012. Abstract 1172. 2. Krishnan P, et al. Antimicrob Agents Chemother. 2015;59:979-987. 3. Yang G, et al. EASL 2013. Abstract 1199. 4. Ng T, et al. CROI 2014. Abstract 639.
Resistance Analysis of Select NS5A Inhibitors in Genotype 1 HCV
> 100 x 3 to 100 x < 3 x
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
NS5A RAVS with < 100 x resistance
Sarrazin C. AASLD 2014. Abstract 1926.
Impact of Duration of LDV/SOF on SVR12 in Pts With Baseline NS5A Resistance
10080
60
40
20
0
10080
60
40
20
0
100 83 95
10065
95 100 100 99
100 92 96100 96 97
12/12
24/29
184/193
110/116
11/17
5/5
27/27
44/46
362/373
95/96
6/6
7/7
8/8
24/25
174/183
8 Wks 12 Wks 24 Wks
Treatment Naive
Treatment Experienced
12 Wks 24 Wks
SVR
12 (%
)SV
R12
(%)
n/N =
n/N =
NS5A RAVS with > 100 x resistance No NS5A RAVs
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Durability of Treatment-Emergent NS5A RAVs After Virologic Failure Study of pts not achieving SVR after receiving LDV without SOF
NS5A RAVs persisted in majority of pts for 96 wks
100
80
60
40
20
0VF Baseline FU-12 FU-24 FU-48 FU-96
98 100 98 100 9586
Pts
With
NS5
A R
AVs
(%)
Registry Study
62/63
58/58
42/43
45/45
52/55
50/58
n/N =
Dvory-Sobol H, et al. EASL 2015. Abstract O059.
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Pooled Analysis: RAV Persistence After Failure of PTV/RTV-, OMV-, DSV-Based Tx
100
80
60
40
20
0
PTV-Containing Regimens
Any D168 R155K
46
9
38
77
29
4
100
80
60
40
20
0
OMV-Containing Regimens
Any M28V/T Q30E/K/R
97 96 97 10093 89
100
80
60
40
20
0
DSV-Containing Regimens
Any S556G
75
90
57
77
Follow-up Wk 24 Follow-up Wk 48
n/N = n/N = n/N = 31/67 5/57
21/55 2/53
10/13 2/7
68/70
32/33
38/41
49/51
21/21
25/28
33/44
27/30
20/35
17/22
RA
Vs (%
)
RA
Vs (%
)
RA
Vs (%
)
NS3/4A Position NS5A Position NS5B Position
Krishnan P. EASL 2015. Abstract O057.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
92100
91
0/1200/218
AVIATOR: No Impact of Baseline RAVs in GT1a Pts Treated With OMV/PTV/RTV + DSV Treatment naive pts or null responders to previous pegIFN/RBV
All differences in SVR24 with vs without baseline RAVs were nonsignificant
Krishnan P, et al. Antimicrob Agents Chemother. 2015;59:5445-5454.
100
80
60
40
20
0
NS3 RAVs
Q80K D168
88 94
0
92100
80
60
40
20
0
NS5A RAVs
M28V/T Q30R L31V
86 92
100
91100
80
60
40
20
0
NS5B RAVs
S556G C316Y
100
50
93
With RAV
n/N = n/N = n/N = 12/14
3/3
1/1
192/209
201/220
203/222
7/7
1/2
220/239
226/244
Y93C/N/H
8092
4/5
200/218
78/89
122/130
SVR
24 (%
)
SVR
24 (%
)
SVR
24 (%
)
Without RAV
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Wyles DL, et al. Hepatology. 2015;61:1793-1797.
GT1 HCV with previous SOF
failure (29% cirrhotic)*
(N = 51)
LDV/SOF + RBV
12 Wks
*25 pts (49%) were previously treated with SOF + pegIFN/RBV, 21 (41%) with SOF ± RBV, 5 (10%) with SOF placebo plus pegIFN/RBV or GS-0938 monotherapy, 1 (2%) with SOF monotherapy.†1 pt who relapsed found to have GT3a HCV infection and enrolled in error.
SVR12, %
98†
LDV/SOF + RBV in GT 1 HCV Pts With Previous Failure on Sofosbuvir Regimens Phase II trial
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GT1 HCV–infected pts with and without cirrhosis previously treated with 8 or 12 wks of LDV/SOF ± RBV or LDV/SOF + GS-966
24 Wks of LDV/SOF Retreatment After Failure of 8-12 Wks of LDV/SOF-Based Tx
Lawitz E, et al. EASL 2015. Abstract O005.
Previous Tx Duration
100
80
60
40
20
0
SVR
12 (%
)
All No Yes
71 6874
15/22
14/19
No Yes8 Wks 12 WksCirrhosis BL NS5A RAVs
80
46
60
100
24/30
5/11
11/11
18/30n/N =
29/41
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24 Wks of LDV/SOF After Failure of LDV/ SOF-Based Tx: Effect of Baseline RAVs
NS5B variants emerged during retreatment in 33% of pts (4/12) with virologic failure
– S282T: n = 2; L159F: n = 1; S282T + L159F: n = 1Lawitz E, et al. EASL 2015. Abstract O005.
SVR12 by Baseline NS5A RAVs, n/N (%) LDV/SOF for 24 WksNumber of RAVs 0 11/11 (100) 1 11/16 (69) ≥ 2 7/14 (50)
Single NS5A RAV Q30R or M28T 5/5 (100) L31M 4/5 (80) Y93H/N 2/6 (33)
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GT1 Pts With NS5A Failure: Who Needs Resistance Testing? If previous failure of any NS5A inhibitors (including DCV + SOF,
LDV/SOF, OMV/PTV/RTV + DSV) and minimal liver disease, deferral preferred pending further data
– If cirrhosis or other need for urgent treatment, test for NS3 and NS5A RAVs
Applies to genotype 1a and 1b HCV infection
NS3 and NS5A testing not required for:
– Previous failure of NS3/4A PIs (including simeprevir, boceprevir, telaprevir)
– Previous failure of NS5B inhibitors (sofosbuvir)
– Tx-naive pts (unless considering SMV + SOF in cirrhotic GT1a)AASLD/IDSA/IAS-USA. HCV Guidance.
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Selecting Treatment Based on Resistance Testing Results If genotype 1a or 1b HCV infection and previous failure
with any NS5A inhibitors and cirrhotic or other need for urgent treatment:
AASLD/IDSA/IAS-USA. HCV Guidance.
RAV Testing Result Retreatment Regimen DurationNo NS5A RAVs Ledipasvir/sofosbuvir + ribavirin 24 wksNS5A but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 wksNS5A and NS3 RAVs Retreatment in a clinical trial setting
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Is Ribavirin Required for Pts With Cirrhosis? Integrated analysis of > 500 pts with cirrhosis treated with LDV/SOF ± RBV
Treatment-experienced pts had previously received HCV PI
Although NS5A resistance not measured, RBV overcomes shorter treatment duration in patients with HCV cirrhosis and prior treatment failure
SVR12, % Total(N = 513)
Treatment Naive(n = 161)
Treatment Experienced(n = 352)
Overall 96 98 95
12 wks ± RBV 95 97 94
24 wks ± RBV 98 99 98Without RBV 95 96 95With RBV 97 99 9612 wks without RBV 92 96 9012 wks with RBV 96 98 9624 wks without RBV 98 97 9824 wks with RBV 100 100 100
Reddy KR, et al. Hepatology. 2015;62:79-86.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
Is Ribavirin Required for Pts With Cirrhosis and NS5A RAVs? Integrated analysis of > 500 pts with cirrhosis treated with
LDV/SOF ± RBV
Treatment experienced patients had previously received HCV PI
SVR12, % (n/N)18 With NS5A RAVs Without NS5A RAVsOverall 91 (86/94) 98 (407/417)12 wks without RBV 88 (23/26) 95 (86/91)12 wks with RBV 94 (32/34) 97 (164/169)24 wks without RBV 85 (17/20) 100 (113/113)24 wks with RBV 100 (14/14) 100 (44/44)
Reddy KR, et al. Hepatology. 2015;62:79-86.
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Personal Recommendations for Resistance in GT3 and GT4 HCV Infection Genotype 3
– Treatment failures on daclatasvir should be tested for NS5A RAVs
– BOSON: Adding pegIFN to SOF/RBV appears to help overcome virologic failure due to resistance in GT3[1]
– Improved SVR12 vs SOF/RBV alone in both treatment-naive and treatment-experienced pts, with or without cirrhosis
Genotype 4– Resistance testing should be performed if considering
retreatment after LDV/SOF failure
– Use SMV/SOF/RBV for NS5A RAVs1. Foster GR, et al. EASL 2015. Abstract LO5.
clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy
Summary Baseline RAVs (especially NS5A) are present in treatment-naive pts
Treatment-emergent RAVs (including multidrug-resistant RAVs) seen in treatment failure and in all DAA classes and rarely with SOF
NS3 RAVs have low replication efficacy and disappear over 9-18 mos
– If considering SMV + SOF: In treatment-naive and treatment-experienced pts with both genotype 1a HCV infection and compensated cirrhosis, ensure no Q80K
NS5A treatment-emergent RAVs persistent and a clinical challenge
– If failure with any NS5A inhibitors (including DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV), and treatment is urgent, test for NS3 and NS5A RAVs
– Use SMV + SOF + RBV if NS5A but no NS3 RAVs
– Use LDV/SOF + RBV if no NS5A RAVs
– Treat in clinical trial if both NS5A and NS3 RAVs present
Resistance testing may be of benefit in treatment failures
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