Resistance to DAA’s before and after treatment Course Presentations/Dieterich...Do you think DAA...
Transcript of Resistance to DAA’s before and after treatment Course Presentations/Dieterich...Do you think DAA...
Resistance to DAA’s before and after treatment
Douglas T. Dieterich, M.D
Professor of Medicine Division of Liver Diseases,
Icahn School of Medicine at Mount Sinai
Disclosure
• Dr Dieterich has served as a consultant or scientific advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Idenix Pharmaceuticals, Inc, Merck & Co, Inc, and Janssen Therapeutics. He has received grants or research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck & Co, Inc, and Janssen Therapeutics (Updated 02/17/14)
Do you think DAA resistance is important to know about now?
• I have a pt w harvoni failure.
• Q80k positive (although seems SIM resistance is not predicted) and q30h y93h also positive.
• Can only think to give peg riba sovaldi or sovaldi riba unless you have any clinical trials w daa. I could ask for sim sof but the argument may be muted since recent guidelines suggest that patients with both NS5,3 ravs be referred to clinical trials.
• She is child A. Really appreciate any help she can get.
Virologic Barriers to Resistance
Genetic barrier Number and type of nucleotide changes required for a virus to
acquire resistance to an antiviral regimen[1]
Viral fitness Relative capacity of a viral
variant 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]
1
.75
.5
.25
0
% F
itn
ess
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
virus
Resistant
virus
Antiviral
therapy
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.
Q80
R155
D168
A156
F43
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.
SV
R1
2 (
%)
100
80
60
40
20
0
97 95 96
112/
115
38/
40
44/
46
68/
70 n/N =
Naive Exp’d
Treatment History
HCV GT
1a + Q80K
1a no Q80K
97
150/
155
All pts
88
79 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
0
n/N =
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.
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 DAAs
AASLD/IDSA/IAS-USA. HCV Guidance.
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 Wks
LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF
SV
R12 (
%)
100
80
60
40
20
0
93 94 96 97 100 98 98 100
Failure of pegIFN/RBV
Failure of PI
Treatment History
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
Fold-Change in EC50 Genotype 1a Genotype 1b
Position M28T Q30R L31M/V Y93H/N L31V Y93H/N
FDA approved
Daclatasvir[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
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
100
80
60
40
20
0
100
80
60
40
20
0
100 83 95
100
65 95 100 100 99
100 92 96 100 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
SV
R1
2 (
%)
SV
R1
2 (
%)
n/N =
n/N =
NS5A RAVS with > 100 x resistance No NS5A RAVs
ALLY-1: Multicenter, Open-Label Phase 3 Study
18 a HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12 by Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL).
Follow-up
DCV 60 mg QD + SOF 400 mg QD + RBV
Week 0 Week 24 SVR12a
Week 36
DCV 60 mg QD + SOF 400 mg QD + RBV
Week 12
Advanced cirrhosis N = 60
Post-liver transplant N = 53
• Primary endpoint: SVR12 in GT1 in each cohort
• 12 weeks of treatment: DCV 60 mg + SOF 400 mg + RBV – RBV initially 600 mg/day, adjusted to 1000 mg/day based on Hgb levels and CrCl
• Advanced cirrhosis patients with treatment interrupted by liver transplantation could receive an additional 12 weeks of treatment immediately post-transplant
SVR12 by Cohort
19 a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals.
82 95
0
20
40
60
80
100
SVR
12
, %a
Post-transplant Advanced cirrhosis
SVR12 by Cohort
83 94
0
20
40
60
80
100
Post-transplant Advanced cirrhosis
All Patients GT 1 (Primary Endpoint)
■ In a regression analysis, no difference by gender, age, IL28B, or HCV RNA
in the advanced cirrhosis cohort with GT 1
Baseline resistance polymorphisms
• NS5A-28, -30, -31, or -93 polymorphisms detected in 22 of 112 patients – 82% (18/22) achieved SVR12
• 10/14 in cirrhosis cohort; 8/8 in post-transplant cohort
– 90% (81/90) without NS5A polymorphisms achieved SVR12 • 39/45 in cirrhosis cohort; 42/45 in post-transplant cohort
• No NS5B-S282 variants detected at baseline or failure
NS5A resistance-associated variants in patients with virologic failure
20
Resistance Analyses
Advanced cirrhosis Post-transplant
Virologic failures, N 10 3
NS5A RAVs at baseline, n/Na 4/10 0/3
NS5A RAVs at failure, n/Na 10/10 3/3 a Assessed by population-based sequencing.
92
100
91
0/1
200/
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
92 100
80
60
40
20
0
NS5A RAVs
M28V/T Q30R L31V
86 92
100
91 100
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
80
92
4/
5
200/
218
78/
89
122/
130
SV
R2
4 (
%)
SV
R2
4 (
%)
SV
R2
4 (
%)
Without RAV
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
0 VF Baseline FU-12 FU-24 FU-48 FU-96
98 100 98 100 95
86
Pts
Wit
h N
S5A
RA
Vs
(%)
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.
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 97 100
93 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.
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
• 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
SV
R12 (
%)
All No Yes
71 68 74
15/ 22
14/ 19
No Yes 8 Wks 12 Wks
Cirrhosis BL NS5A RAVs
80
46
60
100
24/ 30
5/ 11
11/ 11
18/ 30 n/N =
29/ 41
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 = 1
Lawitz E, et al. EASL 2015. Abstract O005.
SVR12 by Baseline NS5A RAVs, n/N (%) LDV/SOF for 24 Wks
Number 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)
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.
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 Duration
No NS5A RAVs Ledipasvir/sofosbuvir + ribavirin 24 wks
NS5A but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 wks
NS5A and NS3 RAVs Retreatment in a clinical trial setting
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 98
Without RBV 95 96 95
With RBV 97 99 96
12 wks without RBV 92 96 90
12 wks with RBV 96 98 96
24 wks without RBV 98 97 98
24 wks with RBV 100 100 100
Reddy KR, et al. Hepatology. 2015;62:79-86.
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 RAVs
Overall 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.
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 RAVs
1. Foster GR, et al. EASL 2015. Abstract LO5.
CONCLUSIONS • Approved treatments work extremely well (96%)
• There are some patients who fail however
• Resistance to NS5A inhibitors, both baseline and acquired is becoming more important
• Resistance testing is recommended after failure of any NS5A containing regimen
• In addition, repeat Genotyping should be done to make sure that you treated the correct genotype or that there are not multiple or recombinant genotypes.