Jorge L. Herrera, MD, MACG
HCV – Retreatment of DAA FailuresJORGE L. HERRERA M.D., MACG
UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE, MOBILE, AL
DAA Drug ClassesNS3/4 (protease) inhibitors◦ Telaprevir, boceprevir, simeprevir,
paritaprevir◦ Coming soon: grazoprevir
NS5a Inhibitors◦ Ledipasvir, dasabuvir, Daclatasvir◦ Coming soon: Elbasvir, velpatasvir
NS5b (polymerase) ◦ Sofosbuvir (nucleoside)◦ Ombitasvir (non-nucleoside)
In general:Resistance is shared among classes◦ New generation drugs may
overcome resistance within class
Resistant mutants are sensitive to drugs from other classes◦ Basis for multiple drug cocktails
New generation drugs within a class may overcome existing resistance
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Jorge L. Herrera, MD, MACG
Barrier to ResistanceDrug Class Examples Barrier to Resistance
Protease inhibitors Telaprevir, boceprevir, simeprevir, paritaprevir
++
Protease inhibitors 2nd
generationGrazoprevir +++
NS5a inhibitors Ledipasvir, ombitasvir, daclatasvir
++
Nucleoside NS5b inhibitors
Sofosbuvir ++++++
Non-nucleoside NS5b Inhibitors
Dasabuvir +
+ = very low barrier to resistance ++++++ = very high barrier to resistance
Schaefer EA, et al. Gastroenterology 2012;142:1340-1350
Determinants of barrier to resistanceNumber of mutations needed to become resistant◦ 1st Generation protease inhibitors◦ Genotype 1a – 1 mutation◦ Genotype 1b – 2+ mutations
Fitness of the resultant mutant◦ Nucleoside polymerase inhibitor-resistant mutant – very unfit◦ Protease inhibitor-resistant mutant – retain some fitness◦ Non-nucleoside polymerase inhibitor mutants – remain fit◦ NS5a – remain fit
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Jorge L. Herrera, MD, MACG
Persistence of Resistance After Failure to Pr/O/DGenotype 1a patients
Persistence assessed 48 weeks after discontinuation of therapy
Resistance Mutation Percent Persisting at 48 wkNS3 9%
NS5b (non-nucleoside) 57%NS5a 96%
Krishnan P, et al. J Hepatol 2015;62:S220, Abstract O057
Informs decision-making process on how to re-treat prior failures
Resistant Variants are Selected During Therapy
XX
Sensitive (wild) virus Resistant virus
Baseline Antiviral TherapyResistant
variants expand
Pawlotsky JM. Clin Liv Dis 2003;7:45-66
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Jorge L. Herrera, MD, MACG
Clinical Management of DAA Failures
Clinical Practice ScenariosFailedIFN + boceprevir, telaprevir or simeprevir
IFN + sofosbuvir + ribavirin
Sofosbuvir + ribavirin
Sofosbuvir + simeprevir
Sofosbuvir + ledipasvir
Paritaprevir + ombitasvir + dasabuvirLevel of Difficulty
+
-
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Jorge L. Herrera, MD, MACG
PEG-IFN +Telaprevir/Boceprevir/Simeprevir Failures
93%100%
94% 98%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 weeks 24 weeks
Sofosbuvir + Ledipasvir for Prior Treatment Failure
P+R P+R+PI
40/43 62/66 58/58 49/50
Afdhal N, et al. NEJM 2014;370:1483-93
Grazoprevir (PI) + Elbasvir (NS5a) + Ribavirin for Prior PI Failure79 patients (34 cirrhosis), prior failure to PEG + Ribavirin + either:◦ Boceprevir◦ Telaprevir◦ Simeprevir
12 week therapy with grazoprevir, elbasvir and ribavirin
SVR12 rates:◦ Overall: 96% (76/79)◦ Prior virologic failure: 95.5% (63/66)◦ Baseline NS3 RAVs: 91.2% (31/34)◦ Baseline NS5a RAVs: 75% (6/8)
Forns X, et al. J Hepatol 2015;63:564-572
FDA Indication for PI failures
Grazoprevir + Ribavirin 12 weeks
AASLD Guidance: 16 weeks if RAV’s
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Jorge L. Herrera, MD, MACG
G1 Sofosbuvir Regimen Failures(NS5a-free regimens)
Management of prior sofosbuvir failures◦ PEG-IFN + Sofosbuvir + ribavirin◦ Sofosbuvir + ribavirin
Sofosbuvir-resistant mutants (S282T) are very rare◦ Extremely unfit◦ Do not survive
Retreated with◦ Sofosbuvir + ledipasvir + ribavirin 12 weeks
SVR-12: 98% (44/45)*
*The failure patient was a G3 patient that was misclassified
Wyles D, et al. Hepatology 2015;61:1793-1797
Is Ribavirin Needed in Sofosbuvir Failures?14 patients, G1, prior failures to 24 weeks of sofosbuvir + ribavirin
Re-treatment: Sofosbuvir + ledipasvir 12 weeks
Responses included◦ 1 patient with detectable S282T mutation pre-therapy◦ 7 with cirrhosis
SVR-12: 100%
Osinusi A, et al. Ann Intern Med 2014;161:634-638
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Jorge L. Herrera, MD, MACG
AASLD/IDSA Guidance
No Cirrhosis◦ Ledipasvir + sofosbuvir – 12 weeks◦ Daclatasvir + sofosbuvir – 12 weeks◦ Grazoprevir + elbasvir + ribavirin – 12-16 weeks
Compensated Cirrhosis◦ Ledipasvir + sofosbuvir + ribavirin – 12 weeks◦ Ledipasvir + sofosbuvir – 24 weeks◦ Daclatasvir + sofosbuvir + ribavirin – 24 weeks◦ Grazoprevir + elbasvir + ribavirin – 12-16 weeks
Telaprevir, Boceprevir or Simeprevir + PEG-IFN Failures G1
Hcvguidelines.org accessed May 16, 2016
AASLD/IDSA Guidance
No Cirrhosis◦ Ledipasvir + sofosbuvir + ribavirin 12 weeks
Compensated Cirrhosis◦ Ledipasvir + sofosbuvir + ribavirin – 24 weeks
G1 Prior Sofosbuvir Failures (no NS5a)PegIFN + sofosbuvir + ribavirin or sofosbuvir + ribavirin
Hcvguidelines.org accessed May 16, 2016
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Jorge L. Herrera, MD, MACG
G1 Failures to Sofosbuvir + SimeprevirDefer therapy if possibleIf cirrhosis or urgent need for therapy:◦ Test for NS3 and NS5a resistance◦ If using a sofosbuvir based regimen with two drugs◦ Use ribavirin, treat for 24 weeks
◦ Best to use a sofosbuvir-based triple or quadruple DAA regimen
Hcvguidelines.org accessed May 16, 2016
NS5a-Experienced PatientsLEDIPASVIR, DACLATASVIR, OMBITASVIR
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Jorge L. Herrera, MD, MACG
Resistance Analysis of Select NS5A Inhibitors in G1 HCV
1. Cheng G, et al. EASL 2012, Abstract 11722. Krishnan P, et al. Antimicrob Agents Chemother 2015;59:979-9873. Yang G, et al. EASL 2013. Abstract 11994. NG T, et al. CROI 2014, Abstract 639
Persistence of Treatment-Emergent NS5a RAVs
Study of patients not achieving SVR after therapy with LDV without SOF
NS5a RAVs persisted in majority of patients for 96 weeks
Dvory-Sobol H, et al. EASL 2015. Abstract O059
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Jorge L. Herrera, MD, MACG
Prevalence of RAVs in DAA-experienced Patients
10%
14%
41%
6%
19%
4%
1%5%
61%32%
3%2%2%
No RAVsNS5ANS3 + NS5ANS5A + NS5BNS3NS5BNS3 + NS5BNS3 + NS5A + NS5B
German Resistance Database: 310 patients with IFN-free DAA regimen failures
G1 (N=195): 90% with RAVs
G3 (N=69): 39% with RAVs
Vermehren J et al. EASL 2016, Abstract PS103 Slide credit: clinicaloptions.com
Re-treatment of Sofosbuvir/Ledipasvir Failures
100%
60%
0%10%20%30%40%50%60%70%80%90%
100%
SVR-12
No NS5a RAV's NS5a RAV's Present
11/11 18/30
Failed 8-12 weeks, re-treated with 24 weeks of ledipasvir + sofosbuvir
Lawitz E, et al. J Hepatol 2015;62:S192, Abstract O005
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Jorge L. Herrera, MD, MACG
Re-Treatment of LDV/SOF Failures – Effect of Baseline RAVs
NS5b variants (S282T) emerged during retreatment in 4/12 patients with virologicfailure
Lawitz E, et al. EASL 2015, Abstract O005
Re-Treatment of NS5a Containing Regimen FailuresData is very limitedPersistence of NS5a resistant polymorphism is likely◦ Particularly if prior treatment was >12 weeks
Co-existence of NS3 resistant polymorphisms affects choice of therapyPre-treatment resistance testing important
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Jorge L. Herrera, MD, MACG
Treatment of Genotype 1 NS5a-Experienced Patients AASLD/IDSA Guidance
If mild liver disease◦ Defer treatment until data available
Cirrhosis or need for urgent therapy◦ Test for NS3 and NS5a resistance-associated variants (RAVs)
RAV Testing Result Retreatment Regimen Duration
No NS5a RAVs Ledipasvir/sofosbuvir + ribavirin 24 weeks
NS5a but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 weeks
NS5a and NS3 RAVs Refer to clinical trial
Testing for Resistance is Commercially AvailableResistance Panel Quest LabCorp
NS3 90924 550540
NS5a 92447 550325
NS5b 92204 550505
Currently, testing is only available for genotype 1
Controversies How accurate are these tests? How many mutations are too many?Which mutations do we need to pay attention to?
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Jorge L. Herrera, MD, MACG
Mutations of Importance for NS5a experienced Patients
Paritaprevir/Ombitasvir/DasabuvirFailuresFew data availablePatients who have failed often have resistance to◦ NS3◦ NS5a◦ NS5b
Defer therapy if mild liver diseaseTest for resistance if therapy needed now◦ Design a sofosbuvir-based regimen
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Jorge L. Herrera, MD, MACG
Genotype 2 FailuresPEG-IFN + ribavirin failures – No Cirrhosis◦ Sofosbuvir + ribavirin 12 weeks◦ Sofosbuvir + daclatasvir 12 weeks if ribavirin ineligible
PEG-IFN + ribavirin failures – Compensated cirrhosis◦ Sofosbuvir + ribavirin – 16 to 24 weeks◦ Sofosbuvir + daclatasvir – 16 to 24 weeks if ribavirin ineligible
Sofosbuvir + ribavirin failures + cirrhosis◦ Sofosbuvir + daclatasvir + ribavirin for 24 weeks
AASLD/IDSA Guidance Document
Hcvguidelines.org accessed May 16, 2016
Genotype 3 FailuresPEG-IFN + ribavirin failures – no cirrhosis◦ Daclatasvir + sofosbuvir – 12 weeks◦ Sofosbuvir + ribavirin + PEG-IFN – 12 weeks
PEG-IFN + ribavirin failures – compensated cirrhosis◦ Daclatasvir + sofosbuvir + ribavirin – 24 weeks◦ Sofosbuvir + ribavirin + PEG-IFN for 12 weeks
Sofosbuvir + Ribavirin failures - + cirrhosis◦ Daclatasvir + Sofosbuvir + ribavirin – 24 weeks ◦ Sofosbuvir + ribavirin + PEG-IFN – 12 weeks
AASLD/IDSA Guidance Document
Hcvguidelines.org accessed May 16, 2016
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Jorge L. Herrera, MD, MACG
Future OptionsEASL 2016
SOF/VEL + GS-9857 – 12 wkDAA Treatment experienced (G1: 73%)
100% 100% 100% 98%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Genotype 1 Prior NS5A >2 DAA Classes Cirrhosis
SVR
63/63 35/35 65/65 60/61
Lawitz E, et al. EASL 2016. Abstract PS008 Slide credit: clinicaloptions.com
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Jorge L. Herrera, MD, MACG
SOF/VEL + GS-9857 – 12 wkDAA Treatment experienced
100%92%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Genotype 2 Genotype 3 Genotype 4
SVR
11/11 11/12 4/4
Lawitz E, et al. EASL 2016. Abstract PS008 Slide credit: clinicaloptions.com
ABT-493(PI) + ABT-530(NS5A) +Ribavirin 12wk in DAA-Experienced Patients
N=50
Prior Therapy◦ PI but no NS5a: 50%◦ NS5b: 54%◦ PI and NS5a: 34%◦ NS5a but no PI: 16%
82% had NS3 and/or NS5a RAVs at baseline
100
80
60
40
20
0
95 95
20/21 19/20
mIT
T S
VR
12 (
%)
ABT-493:ABT-530:
RBV:
20080-
100
6/6
300120800
300120
-
n/N =
Poordad F, et al. EASL 2016. Abstract GS11 Slide credit: clinicaloptions.com
92% of patients with >2 RAVs achieved SVR
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Jorge L. Herrera, MD, MACG
Take Home Points1. Fortunately, the majority of treated patients are cured!
2. Get it right the first time!
3. For the second time around◦ Treatment is easy if failed a 1st generation PI◦ Options are good if failed sofosbuvir + ribavirin◦ Use pre-treatment RAVs testing for failures to◦ NS5a◦ Non-nucleoside NS5b
4. Refer to the HCV guidance document for latest updates
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