HCV: Re-treatment of DAA Failuress3.gi.org/meetings/na2016/16ACG_Hep_School_Southern_0007.pdf · 24...

Tram T. Tran, MD, FACG

HCV: Re-treatment of DAA Failures

Tram T. Tran, MD, FACGProfessor of Medicine

Medical Director, Liver TransplantCedars Sinai Medical Center

• GT1 HCV–infected pts with and without cirrhosis previously treated with 8 or 12 wks of LDV/SOF ± RBV or LDV/SOF + GS-9669

Retreatment with longer therapy:24 weeks SOF/LED

Lawitz E, et al. EASL 2015. Abstract O005. Previous Tx

Duration

100

80

60

40

20

0

SV

R12

(%

)

All No Yes

71 6874

15/22

14/19

No Yes8 Wks 12 WksCirrhosis BL NS5A RAVs

80

4660

100

24/30

5/11

11/11

18/30n/N =

29/41

ACG 2016 Southern Hepatitis School Copyright 2016 American College of Gastroenterology

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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 = 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)

DAA Salvage: Triple Combination• Sofosbuvir (SOF)1,2

–Potent antiviral activity against HCV GT 1–6• Velpatasvir (GS-5816; VEL)3-5

–HCV GT 1–6–2nd-generation NS5A inhibitor with improved resistance

profile

• Voxilaprevir (GS-9857)6,7

–HCV NS3/4A protease inhibitor –Improved resistance profile

FDC, fixed-dose combination1. Jacobson IM, et al. N Engl J Med 2013;368:1867-77; 2. Lawitz E, et al. N Engl J Med 2013;368:1878-87; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. J Viral Hepat 2015;22:1011-9; 6. Taylor JG, et al. EASL 2015, poster 899; 7. Kirby B, et al. EASL 2015, poster 861. 4


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Study DesignGS-US-367-1168 and GS-US-367-1169

• Two Phase 2, multicenter, open-label studies (US, New Zealand) – GS-US-367-1168: GT 1 – GS-US-367-1169: GT 2, 3, 4, 5, 6

• Broad inclusion criteria– HCV treatment experienced, including DAA experienced

• GT 1: NS5A inhibitor or ≥2 DAA classes • GT 2–6: Peg-IFN + RBV or any DAA

– 50% with compensated cirrhosis5

0 12 24

SVR12SOF/VEL + GS-9857N=128

Week

Results: Prior Treatment Experience (N=128)

*GT 2-6 patients who failed prior Peg-IFN + RBV regimens.

NS3 NS5A NS5B NUC NS5B NNUC

1%

11%

1%

4%

6%

2%

24%

1%

3%

24%NS5A27%n=35 Non-NS5A

52%n=66

DAA Naïve*21%n=27

2%


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99 100 100 97 100

0

20

40

60

80

100

Results: SVR12 Overall and by Genotype

7

SV

R12

(%

)

♦ One patient relapsed at post-treatment week 8♦ 58-year-old white female with GT 3a infection, HCV RNA 7.0 log10

IU/mL, and cirrhosis

Overall GT 3GT 2 GT 4, 6GT 1

63/63127/128 9/934/3521/21

Results: Resistance Analysis

*Deep sequencing with 1% assay cutoff.

99%SVR12

100%SVR12

51/51

99%SVR12

76/77

40% No Baseline RAVs

(51/128)

60% Baseline RAVs (77/128)

20%NS5A RAVs

only

15% NS3 RAVs

only23%

Multiple classRAVS

2% NS5B RAVs only

Results: Resistance Analysis

*Deep sequencing with 1% assay cutoff.

99%SVR12

100%SVR12

51/51

99%SVR12

76/77

40% No Baseline RAVs

(51/128)

60% Baseline RAVs (77/128)

20%NS5A RAVs

only

15% NS3 RAVs

only

23%Multiple class

RAVS

2% NS5B RAVs only


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1. Ng TI, et al. Abstract 636. CROI, 2014. 2. Ng TI, et al. Abstract 639. CROI, 2014.

DAA Salvage Regimens: Dual Regimen

Glecaprevir (ABT-493) Pangenotypic NS3/4A PIPibrentasvir (ABT-530) Pangenotypic NS5A

• Magellan Study• GT1 non-cirrhotic patients • Failed an NS3 PI and/or NS5A inhibitor-containing

regimen ± sofosbuvir

NS5A Inhibitor Fold Change in EC50 for GT1a NS5A Variants

Q30E L31M/V H58D Y93H/NABT-530 2.4 1.1 – 1.3 1.1 6.7 – 7.1

Ledipasvir1,2 3279 393 – 2787 >1000 4918Velpatasvir3,4 37 2.1 – 9 NA 81 – 609Daclatasvir5 25205 341 – 3386 500 5432 – 47477Elbasvir4,6 50 125 NA 600 – 2000

Ombitasvir7 1326 2 243 41383 – 66740Odalasvir1,4 71 1 – 2.4 8 5083

MK-8408 NA NA NA NANA, not available

ABT-530 Retains Antiviral Activity Against Common GT1a Single-Position NS5A Variants

1. Patel D, et al. EASL, 2015. 2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205834Orig1s000MicroR.pdf3. Doehle BP, et al. EASL, 2015. 4. Gao M, et al. Curr Opin Virol ; 3:514-20.5. Fridell RA, et al. Hepatology,54:1924-35. 6. Gane E, et al. EASL, 2015. 7. Krishnan P, et al. AAC, 2015.


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Treatment experience by DAA class:

Prior DAA Treatment Regimens Among Enrolled

Prior regimen n

LDV/SOF 8SMV + SOF ± RBV 8OBV/PTV/r + DSV ± RBV 4DBV + FDV + RDV ± RBV 4SAM + SMV 2TVR + PR 8BOC + PR 10DCV ± PR 2Other 94 patients were treated more than once with DAA-containing regimens.

PI-expNS5A-naïve

NS5A-expPI-naïve

NS5A-expPI-exp

25 (50%) NS5A-experienced42 (84%) PI-experienced

mITT SVR12 Rates in Patients With Baseline RAVs

* 3 patients with no baseline RAVs were lost to follow-up and are excluded from the mITT analysis. Baseline RAVs based on deep sequencing 1% threshold.

• 100% SVR12 in 10 patients with Y93 NS5A RAVs

• 100% SVR12 in 26 patients with Q80 or R155 NS3 RAVs

• 100% SVR12 in 17 patients with prior failure of a SOF-containing regimen

mITT SVR12 Rates in Patients With Baseline RAVs

* 3 patients with no baseline RAVs were lost to follow-up and are excluded from the mITT analysis. Baseline RAVs based on deep sequencing 1% threshold.

• 100% SVR12 in 10 patients with Y93 NS5A RAVs

• 100% SVR12 in 26 patients with Q80 or R155 NS3 RAVs

• 100% SVR12 in 17 patients with prior failure of a SOF-containing regimen


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Baseline RAVs by Deep Sequencing Detection Threshold: 1% vs 15%

Variants detected by deep sequencing (detection limit of 1%) at the following amino acid positions that confer resistance to at least 1 DAA in the inhibitor class were included in the analysis; they may not confer resistance to ABT-493 or ABT-530.NS3: GT1a: V36A/G/I/L/M, F43L, T54A/S, V55A/I, Y56H, Q80K/R, V107I, S122G/R, I132V, R155(all), A156(all), V158I, D168(all), and I170F/T/V.

GT1b: V36A/G/I/L/M, T54A/C/G/S, V55A, Y56H/L, Q80K/R, V107I, S122A/D/G/I/N/T, R155(all), A156(all), V158I, D168(all), V170A/T, and M175L.NS5A: GT1a: M28(all), Q30(all), L31(all), P32L, H58D/R, and Y93(all). GT1b: L28(all), P29S/del, R30G/H/P/Q, L31(all), P32L/del, P58A/S, Q62D, A92E/K, and Y93(all).

ABT-493 doseABT-530 dose

RBV dose200 mg80 mg

(N = 6)

300 mg120 mg800 mg(N = 22)

300 mg120 mg

(N = 22)

Any NS3 or NS5A RAVs, n (%) 5 (83) 4 [67]

19 (86) 18 [82]

17 (77)15 [68]

NS3 only, n 2, 1 6, 7 7, 7

NS5A only, n 3, 3 6, 6 1, 1

Both NS3 and NS5A RAVs, n 0, 0 7, 5 9, 7

NS3 RAV positions: Q80 (n = 22, 21)R155 (n = 4, 1)D168 (n = 4, 4)

NS5A RAV positions:Q30 (n = 14, 11)Y93 (n = 10, 8)

Most common

Baseline RAVs by Deep Sequencing Detection Threshold: 1% vs 15%

Variants detected by deep sequencing (detection limit of 1%) at the following amino acid positions that confer resistance to at least 1 DAA in the inhibitor class were included in the analysis; they may not confer resistance to ABT-493 or ABT-530.NS3: GT1a: V36A/G/I/L/M, F43L, T54A/S, V55A/I, Y56H, Q80K/R, V107I, S122G/R, I132V, R155(all), A156(all), V158I, D168(all), and I170F/T/V.

GT1b: V36A/G/I/L/M, T54A/C/G/S, V55A, Y56H/L, Q80K/R, V107I, S122A/D/G/I/N/T, R155(all), A156(all), V158I, D168(all), V170A/T, and M175L.NS5A: GT1a: M28(all), Q30(all), L31(all), P32L, H58D/R, and Y93(all). GT1b: L28(all), P29S/del, R30G/H/P/Q, L31(all), P32L/del, P58A/S, Q62D, A92E/K, and Y93(all).

ABT-493 doseABT-530 dose

RBV dose

200 mg80 mg

(N = 6)

300 mg120 mg800 mg(N = 22)

300 mg120 mg

(N = 22)

Any NS3 or NS5A RAVs, n (%) 5 (83) 4 [67]

19 (86) 18 [82]

17 (77)15 [68]

NS3 only, n 2, 1 6, 7 7, 7

NS5A only, n 3, 3 6, 6 1, 1

Both NS3 and NS5A RAVs, n 0, 0 7, 5 9, 7

NS3 RAV positions: Q80 (n = 22, 21)R155 (n = 4, 1)D168 (n = 4, 4)

NS5A RAV positions:Q30 (n = 14, 11)

Y93 (n = 10, 8)Most common

SVR12 by ITT and mITT Analysis

mITTABT-493 200 300 300 200 300 300ABT-530 120 120 120 120 120 120RBV 800 800Breakthrough 0 0 1 0 0 1Relapse 0 1 0 0 1 0LTFU 0 1 2 -- -- --

ITT

1 LTFU after week 6 with HCV RNA undetectable

2 patients LTFU after completing treatment (1 death); both achieved SVR8

SVR1

2, %

Patie

nts

010203040

506070

8090

100100

66

91

1922

2022

86

66

1920

2021

100 95 95


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C SWIFT: Elbasvir/Grazeprevir + Sofosbuvir + Ribavirin


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• Sofosbuvir/Velpatasvir in Combination With Ribavirin for 24 Weeks Is Effective

Retreatment for Patients Who Failed Prior NS5A-Containing DAA Regimens:Results of the Retreatment Study

• Edward J. Gane1, Mitchell L. Shiffman2, Kyle Etzkorn3, Giuseppe Morelli4, Catherine Stedman5, Mitchell N. Davis6, Federico Hinestrosa7, Hadas Dvory-Sobol8, K.C. Huang8, Anu Osinusi8, John McNally8,

Diana M. Brainard8, John G. McHutchison8, Alex Thompson9, Mark Sulkowski10

Abstract 024

EASL 2016 Barcelona

Sofosbuvir/Velpatasvir in Combination With Ribavirin for 24 Weeks Is Effective

Retreatment for Patients Who Failed Prior NS5A-Containing DAA Regimens:Results of the Retreatment Study

Edward J. Gane1, Mitchell L. Shiffman2, Kyle Etzkorn3, Giuseppe Morelli4, Catherine Stedman5, Mitchell N. Davis6, Federico Hinestrosa7,

Hadas Dvory-Sobol8, K.C. Huang8, Anu Osinusi8, John McNally8, Diana M. Brainard8, John G. McHutchison8, Alex Thompson9, Mark Sulkowski10

Abstract 024


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Results: Prior Treatment DetailsSOF/VEL + RBV

N=69

Prior GS-9857, n (%) 28 (41)

Prior VEL dose, n (%)

25 mg 28 (41)

100 mg 41 (59)

Prior treatment duration, n (%)

4 or 6 weeks 25 (36)

8 weeks 26 (38)

12 weeks 18 (26)

Cause of treatment failure, n (%)

Relapse 68 (99)

Mean time to retreatment, days (range) 318 (101–600)

Results: Prior Treatment Details

SOF/VEL + RBVN=69

Prior GS-9857, n (%) 28 (41)

Prior VEL dose, n (%)

25 mg 28 (41)

100 mg 41 (59)

Prior treatment duration, n (%)

4 or 6 weeks 25 (36)

8 weeks 26 (38)

12 weeks 18 (26)

Cause of treatment failure, n (%)

Relapse 68 (99)

Mean time to retreatment, days (range) 318 (101–600)

Results: SVR12 by Genotype91 97 91

76

0

20

40

60

80

100

3334

1317

1314

Total GT 1 GT 2 GT 3

SVR1

2 (%

)

1 relapse*

1 nonresponse2 relapses1 WC1 relapse+

5965

+ Relapse after discontinuing treatment at week 3 *Relapse after discontinuing treatment at Week 8,

Error bars represent 95% confidence intervals; WC, withdrew consent.

Results: SVR12 by Genotype

91 97 9176

0

20

40

60

80

100

3334

1317

1314

Total GT 1 GT 2 GT 3

SVR1

2 (%

)

1 relapse*

1 nonresponse2 relapses1 WC1 relapse+

5965

+ Relapse after discontinuing treatment at week 3 *Relapse after discontinuing treatment at Week 8,

Error bars represent 95% confidence intervals; WC, withdrew consent.


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Results: SVR12 by NS5A RAVs

• 11/13 GT 3 patients with RAVs had Y93H; 9 (82%) achieved SVR12• 5 patients had 2 NS5A RAVs; all 5 achieved SVR12• 3 patients had NS3 RAVs; all 3 achieved SVR12

1% deep sequencing cut-off.

*1 patient could not be sequenced; 1 patients who withdrew consent was excluded.

GT 2 (n=13*)GT 1 (n=34) GT 3 (n=16)

100% SVR

100% SVR

100% SVR

38%No RAVs

5/13

62%RAVs8/13

82%No RAVs

28/34

18%RAVs6/34

19%No RAVs3/16

81%RAVs13/16

100% SVR 77% SVR

10/133/38/85/56/6

96% SVR

27/28

Results: SVR12 by NS5A RAVs

11/13 GT 3 patients with RAVs had Y93H; 9 (82%) achieved SVR125 patients had 2 NS5A RAVs; all 5 achieved SVR123 patients had NS3 RAVs; all 3 achieved SVR12

1% deep sequencing cut-off.

*1 patient could not be sequenced; 1 patients who withdrew consent was excluded.

GT 2 (n=13*)GT 1 (n=34) GT 3 (n=16)

100% SVR

100% SVR

100% SVR

38%No RAVs

5/13

62%RAVs8/13

82%No RAVs

28/34

18%RAVs6/34

19%No RAVs3/16

81%RAVs

13/16

100% SVR 77% SVR

10/133/38/85/56/6

96% SVR

27/28

Summary


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HCV: Re-treatment of DAA Failuress3.gi.org/meetings/na2016/16ACG_Hep_School_Southern_0007.pdf · 24...

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