Jointly provided by the Annenberg Center for Health Sciences
at Eisenhower and Clinical Care Options, LLC
HCV Alert: New Data on
Resistance to DAAs and
Implications for Therapy
Nezam H. Afdhal, MD, FRCPI
Professor of Medicine
Harvard Medical School
Beth Israel Deaconess Medical Center
Boston, Massachusetts
This activity is supported by an independent educational grant
from Janssen Therapeutics.
Image: pockygallery/Copyright©2014 Shutterstock Images LLC. All Rights Reserved
Image: djem/Copyright©2014 Shutterstock Images LLC. All Rights Reserved
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
Virologic Barriers to Resistance
Genetic barrier
 Number and type of nucleotide changes required for a virus to
acquire resistance to an antiviral regimen[1]
Fitness of Polymerase Inhibitor Mutants[2,3]
Viral fitness
% Fitness
 Relative capacity of a viral
variant to replicate in a
given environment
1
.75
.5
.25
0
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
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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]
Antiviral therapy eliminates
sensitive variants
Sensitive virus
Resistant virus
Resistant variants expand
Antiviral
therapy
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
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
HCV NS3/4A Protease Resistance
Q80
R155
D168
F43
A156
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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
Impact of Treatment Exp, Q80K Depends
on Cirrhosis (12 Wks’ SMV + SOF in GT1)
No Cirrhosis (OPTIMIST-1[1])
100
97
97
95
96
Cirrhosis (OPTIMIST-2[2])
97
100
SVR12 (%)
83
80
80
60
60
40
40
20
n/N =
0
150/
155
112/
115
38/
40
44/
46
68/
70
All pts
Naive
Exp’d
1a +
Q80K
1a no
Q80K
Treatment
History
HCV GT
20
n/N =
0
92
88
79
74
86/
103
44/
50
42/
53
25/
34
35/
38
All pts
Naive
Exp’d
1a +
Q80K
1a no
Q80K
Treatment
History
1. Kwo P, et al. EASL 2015. Abstract LP14. 2. Lawitz E, et al. EASL 2015. Abstract LP04.
HCV GT
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
ION-2: DAAs Effective Against NS3 RAVs
After Boceprevir or Telaprevir
100
93
94
96
97
100
98
98
100
Treatment
History
Failure of
pegIFN/RBV
SVR12 (%)
80
Failure of PI
60
40
20
0


40/
43
62/
66
45/
47
62/
64
LDV/SOF LDV/SOF + RBV
12 Wks
58/
58
49/
50
LDV/SOF
58/
59
51/
51
LDV/SOF + RBV
24 Wks
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
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
ION-2: NS3 RAVs After Boceprevir or
Telaprevir Respond to DAAs
100
93
94
96
97
100
98
98
100
Treatment
History
Failure of
pegIFN/RBV
SVR12 (%)
80
60
Failure of PI
40
20
40/
43
62/
66
45/
47
62/
64
58/
58
49/
50
58/
59
51/
51
0
LDV/SOF LDV/SOF + RBV
12 Wks


LDV/SOF
LDV/SOF + RBV
24 Wks
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
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
Resistance Analysis of Select NS5A
Inhibitors in Genotype 1 HCV
Fold-Change in EC50
Position
Genotype 1a
Genotype 1b
M28T
Q30R
L31M/V
Y93H/N
L31V
Y93H/N
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
Ombitasvir[2]
> 1000 x
> 100 x
FDA approved
> 100 x
<3x
> 100 x
3 to 100 x
> 10,000 x
> 1000 x/?
< 10 x
< 100 x
<3x
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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
Impact of Duration of LDV/SOF on SVR12
in Pts With Baseline NS5A Resistance
NS5A RAVS with < 100 x resistance
SVR12 (%)
100
100
83
95
24/
29
184/
193
Treatment Naive
100 96
97
100
92
96
8/
8
24/
25
174/
183
80
60
40
20
n/N =
0
12/
12
8 Wks
100
SVR12 (%)
NS5A RAVS with > 100 x resistance
27/
27
44/
46
362/
373
12 Wks
Treatment Experienced
100
95
100
24 Wks
100
99
6/
6
95/
96
65
80
60
40
20
n/N =
0
5/
5
11/
17
110/
116
12 Wks
Sarrazin C. AASLD 2014. Abstract 1926.
7/
7
24 Wks
No NS5A RAVs
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
Durability of Treatment-Emergent NS5A
RAVs After Virologic Failure
Study of pts not achieving SVR after receiving LDV without SOF
100
100
98
98
95
100
Pts With NS5A RAVs (%)

86
80
60
40
20
n/N =
0

62/
63
58/
58
VF
Baseline
42/
43
45/
45
52/
55
FU-12
FU-24
FU-48
Registry Study
NS5A RAVs persisted in majority of pts for 96 wks
Dvory-Sobol H, et al. EASL 2015. Abstract O059.
50/
58
FU-96
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
Pooled Analysis: RAV Persistence After
Failure of PTV/RTV-, OMV-, DSV-Based Tx
Follow-up Wk 24
PTV-Containing Regimens
100
OMV-Containing Regimens
100
97 96 97
100
93
89
100
90
46
38
80
RAVs (%)
60
40
DSV-Containing Regimens
80
77
RAVs (%)
RAVs (%)
80
Follow-up Wk 48
60
40
60
77
75
57
40
29
20
20
9
n/N =
0
31/
67 5/57
Any
21/ 4
55 2/53
10/
13 2/7
D168
R155K
n/N =
NS3/4A Position
Krishnan P. EASL 2015. Abstract O057.
0
20
68/ 49/
70 51
32/ 21/
33 21
38/ 25/
41 28
Any
M28V/T
Q30E/K/R
NS5A Position
n/N =
0
33/ 20/
44 35
27/ 17/
30 22
Any
S556G
NS5B Position
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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
With RAV

All differences in SVR24 with vs without baseline RAVs were nonsignificant
Without RAV
100
88
94
92
86 92
91
100
40
92
91
80
60
40
20
20
0
78/ 122/
89 130
200/
0/1 218
Q80K
D168
n/N =
0
100
93
92
80
SVR24 (%)
SVR24 (%)
SVR24 (%)
60
0
100
80
80
n/N =
100
100
60
50
40
20
12/ 192/
14 209
M28V/T
3/ 201/
3 220
Q30R
1/ 203/
1 222
4/ 200/
5 218
L31V
Y93C/N/H
NS3 RAVs
NS5A RAVs
Krishnan P, et al. Antimicrob Agents Chemother. 2015;59:5445-5454.
n/N =
0
7/ 220/
7 239
1/ 226/
2 244
S556G
C316Y
NS5B RAVs
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
LDV/SOF + RBV in GT 1 HCV Pts With
Previous Failure on Sofosbuvir Regimens
 Phase II trial
12 Wks
GT1 HCV with
previous SOF
failure
(29% cirrhotic)*
(N = 51)
SVR12, %
LDV/SOF + RBV
98†
*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.
Wyles DL, et al. Hepatology. 2015;61:1793-1797.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
24 Wks of LDV/SOF Retreatment After
Failure of 8-12 Wks of LDV/SOF-Based Tx

GT1 HCV–infected pts with and without cirrhosis previously treated with 8 or
12 wks of LDV/SOF ± RBV or LDV/SOF + GS-966
100
100
SVR12 (%)
80
71
68
74
80
60
60
46
40
20
n/N =
0
29/
41
15/
22
14/
19
All
No
Yes
Cirrhosis
Lawitz E, et al. EASL 2015. Abstract O005.
24/
30
5/
11
8 Wks 12 Wks
Previous Tx
Duration
11/
11
18/
30
No
Yes
BL NS5A RAVs
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
24 Wks of LDV/SOF After Failure of LDV/
SOF-Based Tx: Effect of Baseline RAVs
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)
 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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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:
RAV Testing Result
No NS5A RAVs
NS5A but no NS3 RAVs
Retreatment Regimen
Duration
Ledipasvir/sofosbuvir + ribavirin
24 wks
Simeprevir + sofosbuvir + ribavirin
24 wks
NS5A and NS3 RAVs
AASLD/IDSA/IAS-USA. HCV Guidance.
Retreatment in a clinical trial setting
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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
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
With RBV
12 wks without RBV
12 wks with RBV
24 wks without RBV
24 wks with RBV
95
97
92
96
98
100
96
99
96
98
97
100
95
96
90
96
98
100

Although NS5A resistance not measured, RBV overcomes shorter treatment
duration in patients with HCV cirrhosis and prior treatment failure
Reddy KR, et al. Hepatology. 2015;62:79-86.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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
12 wks without RBV
12 wks with RBV
24 wks without RBV
24 wks with RBV
91 (86/94)
88 (23/26)
94 (32/34)
85 (17/20)
100 (14/14)
98 (407/417)
95 (86/91)
97 (164/169)
100 (113/113)
100 (44/44)
Reddy KR, et al. Hepatology. 2015;62:79-86.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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.
HCV Alert: New Data on Resistance to DAAs and Implications for Therapy
clinicaloptions.com/hepatitis
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