Failure after treatment with DAAs: What to...

Failure after treatment with DAAs: What to do?

Marc Bourliere , MD White Nights of Hepatology

Hôpital Saint Joseph Saint Petersburg

Marseille France 2- 3th June 2016

Disclosures

– Board member for : Schering-Plough, Merck, Janssen, Gilead, Boehringer Ingelheim, BMS, Novartis, Roche, AbbVie, GSK, Vertex, Idenix

– Speaker for : Roche, Schering-Plough, Merck, Janssen, Gilead, BMS, Abbvie

Failure is a rare event in the DAAs era: Large real-world data confirm clinical trial results:

16236 GT-1 patients ( EASL 2016)

87% 88% 94%

86%

93% 93% 95% 93% 96% 95% 94% 94% 89%

98% 97% 94%

95%

0%10%20%30%40%50%60%70%80%90%

100%

VA VA / HIV TRIO N Italian Portugese Spanish German

SIM/SOF SOF/LDV 3D SOF/DCV

Nb =2363/4104/773 103/208/13 1378 343/ 73 /42 872 1504/1422 284/1836/390/528

No impact of HIV

HBV, diabetes and

obesity on SVR

Follow the EASL

Guideline

(93% vs 87%)

Hypo Alb <35g/l

negative predictor

of SVR

McCombs J et al: LBP-510,McGinnis J et al: LBP-514, Afdhal N et al: LBP-519, Aghemo A et al: LBP-500, Marinho T et al: LBP-523,

Crespo, J et al: LBP-511, Calleja JL et al: LBP-512, Mauss. S et al: SAT-263

Failure is a rare event in DAAs era even in cirrhotic: Large real-world data confirm clinical trial results: Cirrhotic patients

Deterding K et al. EASL 2016: SAT-194

SAEs : 8.1% and 4 pts died from cirrhosis complication

SVR rates(ITT) : GT-1: 91% , GT-2: 80%, GT-3: 73%, GT-4: 83%

What to do in case of failure ?

Resistance testing ?

Role of Resistance Testing

The presence of resistance associated variants to DAAs prior to treatment may have an impact on SVR, especially in pts with previous DAA treatment experience and/or cirrhosis

Consider resistance testing prior to retreatment in patients who fail to achieve HCV cure with DAA-based treatments

EASL 2015 : recommendation on treatment of Hepatitis C . J Hepatol 2015

Resistance issue

IP

RBV RBV RBV NS5B NUC

NS5A.I I. NNuc NS5B NS5B NNI

Modest barrier

to resistance

(esp to GT1a)

Low barrier

to resistance

(esp to GT1a)

NS5B NUC

Very few or no RAS RASs with

short half-life

NS5A.I

RASs with

long half-life

High barrier

to resistance

NS3/4 PI

NS3/4 PI

Long term follow-up of NS5A RAVs after Ledipasvir failure

• 99% have NS5A RAVs at failure

• Long term follow-up ( up to 2 years after treatment discontinuation by ultra deep sequencing

73 patients included in ledipasvir containing regimen who failed to treatment

➜ NS5A RAVs persist in the majority of patients 2 years after treatment discontinuation

EASL 2015 - D’après Dvory-Sobol H et al., abstr. O059, actualisé

100 % 98 % 100 % 95 %

86 %

0

20

40

60

80

100

Baseline FU 12w FU 24w FU 48w FU 96w

Pa

tie

nts

wit

h R

AV

s (

%)

58/58 42/43 45/45 52/55 50/58

24 Wks of LDV/SOF After Failure of 8-12 Wks of LDV/SOF-Based Therapy in GT1 Pts

Results from single arm of prospective phase II trial

NS5B variants with resistance to SOF emerged during retreatment in 33% of pts (4/12) with virologic failure

– S282T: n = 3 (out of 12)

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

LDV/SOF 90/400 mg QD

GT1 HCV–infected

pts previously treated with

LDV/SOF-based therapy

(N = 41)

24 Wks

100

80

60

40

20

0

SV

R1

2 (

%)

All No Yes

71 68 74

15/

22

14/

19

No Yes 8 Wks 12 Wks

Cirrhosis Previous Tx

Duration BL NS5A RAVs

80

46

60

100

24/

30

5/

11 11/

11

18/

30 n/N = 29/

41

• The re-treatment regimen should contain

• Sofosbuvir because of the high barrier to resistance

• 1 or 2 other DAA(s), if possible with no cross-resistance with the DAA(s) already administered

• Ribavirin

• Treatment duration should be 12 or 24 weeks (recommended in F3-F4)

Re-treatment of Patients who Failed an IFN-Free Regimen

EASL 2015 : recommendation on treatment of Hepatitis C . J Hepatol 2015

German resistance network :

Vermehren J, et al. EASL 2016, Abs. PS103.

No RAS

NS5A

NS3 + NS5A

NS5A + NS5B

NS3

NS5B

NS3 + NS5B

NS3 + NS5A +NS5B

Genotype 1 (n = 195)

No RAS

NS5B

NS5A + NS5B

NS5A + NS5B

NS3 + NS5A

Genotype 3 (n = 69)

RAS in 90 % of patients RAS in 39 % of patients

41 % 4 %

19 %

1 % 5 % 6 % 10 %

14 %

61 %

32 %

2 %

2 % 3 %

Prevalence of RAS in DAAs failure according to genotype

0

20

40

60

80

100

No RAS NS3 NS5A NS5B NS5A +NS5B

NS3 +NS5A

NS3 +NS5B

SMV/SOF failure

n = 27/49 (55 %) 18 %

52 %

15 % 4 % 4 % 7 %

No NS5A RAS

alone

% o

f R

AS

0

20

40

60

80

100LDV/SOF + RBV (n = 10)

100 90

100

SVR

(%

) LDV/SOF + RBV (n = 13)

PrOD + RBV (n = 3)

PrOD + RBV (n = 1)

0 12 24 LDV/SOF + RBV PrOD + RBV

Weeks 12 weeks. 24 weeks. 12 weeks. 24 weeks.

Retreatment with a regimen containing NS5A inhibitors

Intermediate analysis: SVR 12 = 91 % (n = 20/22)

Vermehren J. et al. EASL 2016, Abs. PS103.


0

20

40

60

80

100

No RAS NS3 NS5A NS3 +NS5B

NS5A +NS5B

NS3 +NS5A +NS5B

LDV/SOF failure

n = 11/90 (12 %)

5 %

77 %

No NS3 RAS

alone

% o

f R

ASs

0

20

40

60

80

100SMV/SOF + RBV (n = 6)

100 100

75

SVR

(%

) SMV/SOF + RBV (n = 11)

PrOD + RBV (n = 4)

PrOD + RBV (n = 1)

0 12 24 SMV/SOF + RBV PrOD + RBV


Retreatment with a regimen containing a PI Intermediate analysis: SVR 12 = 86 % (n = 6/7)

DCV/SOF failure

n = 11/29 (38 %)

5 % 9 % 5 %

Q80K

considered as

minor variant



0

20

40

60

80

100

No RAS NS5A NS3 + NS5B NS5A + NS5B NS3 + NS5A+ NS5B

0%

20 %

NO SOF RAS

% o

f R

AS

SOF + LDV + SMV + RBV (n = 1)

SOF + SMV + RBV (n = 1)

SOF + LDV + RBV (n = 3)

0 12 24

weeks

Retreatment with a regimen containing a NS5B Nuc I.

40 %

20 % 20 % PrOD Abbvie failure

n = 5/27 (19 %)



0

20

40

60

80

100

No RAS NS5A (A30K/S)

SOF/RBV failure

n = 14/43 (42 %)

79 %

21 %

% o

f R

AS

0

20

40

60

80

100

DCV/SOF + RBV (n = 3)

100 90 100

SVR

(%

)

DCV/SOF + RBV (n = 10)

LDV/SOF + RBV (n = 1)

0 12 24 DCV/SOF + RBV LDV/SOF + RBV


Retreatment with a regimen containing a NS5A. I. Intermediate analysis: SVR 12 = 100 % (n = 7/7)

No Y93H



Retreatment of HCV DAAs failure according to EASL guidelines

32 patients , 66% F4

Laurain A et al EASL 2016 :FRI- 208

G4

25 %

G1

9%

G3

19 % G2

13 %

G1A

12 %

G1B

22 %

Genotypes repartition • All the patients

were exposed to the NS5B inhibitor during the first line (Sofosbuvir) or ombitasvir.

• All the seconde line have used sofosbuvir base-regimen

First line regimen

SOF/TVR +/- RBV

SOF/TVR +/- RBV

SOF/TVR +/- RBV

SOF/PEG RBV

SOF/PEG RBV

SOF/SMV +/-RBV

SOF/SMV +/-RBV

SOF/DCV +/-RBV

SOF/DCV +/-RBV

SOF/DCV

Each represents a single patient

12 weeks 24 weeks

HCV Genotype

G1 G1A G1B G2 G3 G4

First line of treatment

Secondline of treatment

SOF/PEG RBV

SOF/LDV +/-RBV

SOF/DCV +/-RBV

SOF/DCV +/-RBV

SOF/LDV +/-RBV

SOF/DCV +/-RBV

SOF/LDV +/-RBV

SOF/DCV +/-RBV

SOF/LDV +/-RBV

SOF/DCV +/-RBV

Second line regimen 32 retreated patients 11 during 12 weeks 21 during 24 weeks

100 % SVR12 (21/21)

12 patients under treatment

or follow-up

Retreatment of HCV DAA failures: upon where no to go !!

Geno

type

Baseline

NS3

RAVs

Baselin

e

NS5A

RAVs

Baseli

ne

NS5B

RAVs

Last on-

treatment

HCV RNA

(UI/mL)

SVR12 Failure

NS3

RAVs

Failure

NS5A

RAVs

Failure

NS5B

RAVs

1a R155K,

D168E

M28A,

Q30K

None <12 (EOT) Relapse R155K,

D168E

M28A,

Q30K

None

1a R155K M28T None <12 (EOT) Relapse R155K Q30E None

1a R155K Q30K

None <12 (Week

4)

Relapse

Discontin

uation

due to

SAE*

R155K M28T,

Q30K

None

1a None Q30K

None <12 (EOT) Yes - - -

1b None L28I,

R30S

None <12 (Week

6)

Unknown

Discontin

uation

due to

SAE*

1b None Y93H (S556

G)

<12 (EOT) Yes - - -

1b None None C316N

<12 (EOT) Yes - - -

2 None None None <12 (EOT) Pending

4 D168E L28M,

L30C

None <12 (EOT) Yes - - -

4 None L30S,

Y93H

None <12 (Week

12)

Pending

6 Y56H,

D168C

None None <12 (EOT) Yes - - -

Wk 12 Wk 24 Wk 36

SOF + DCV + SMV + RBV SVR12

Eleven patients (mean age: 56.2 years, range: 48-64)

infected with:

-HCV genotype 1 (1a: n=4 ; 1b: n=3)

-HCV genotype 2 (n=1)



All patients had compensated liver disease (fibroscan: 6.6-

35.3 kPa) and failed to achieve SVR with previous all-oral

regimen

They had received SOF + DCV (n=6) ; DCV + SMV (n=1) ;

SOF + SMV (n= 1) ; SOF + LDV (n=1) ; GRZ + EBV (n=1)

; Mericitabine + Danoprevir + ritonavir (n=1) ; without RBV

for 12 weeks

HCV resistance was assessed at retreatment baseline by

means of population sequencing of the NS3 protease,

NS5A and NS5B polymerase coding regions

- SOF+DCV+SMV+RBV for 24 weeks was associated with on-treatment response in all patients

- However, One patient discontinued early due to SAE (possible mitochondrial toxicity) and virological outcome is pending

- and at least 3 patients failed to achieve an SVR, one due to SAE (pulmonary arterial hypertension), the other two due to post-treatment relapse

- Given the lack of other DAA class options, the latter patients should be considered incurable

Hezode. C et al EASL poster THU-217

• SAEs: Pulmonary arterial hypertension (n=1) ;

• Multi-organ failure possibly related to mitochondrial toxicity (n=1)

RA Substitution (RASs) should be assess before retreatment especially in those who have been treated previously

with PI and NS5A I.

Just Around the Corner

Sofosbuvir/velpatasvir

Gane EJ. Et al. EASL 2016, Abs. PS024

SVR according to RAS and genotype

SOF/VEL + RBV 2 for 24 weeks : A good options for failure to NS5A inhibitors except in genotype 3 patients.

• 11/13 GT-3 patients G3 with Y93H mutations ; 9 (82 %) SVR 12

• 5 patients with 2 NS5A mutations; 5 SVR 12

• 3 patients with NS3 mutations; 3 SVR 12

G1 (n = 34) G2 (n = 13) G3 (n = 16)

82 % No RAS 28/34

38 % No RAS

5/13

19 % No RAS

3/16

18 % RAS 6/34

62 % RAS 8/13

81 % RAS

13/16

96 % SVR

100 % SVR

100 % SVR

100 % SVR

100 % SVR

77 % SVR

27/28 6/6 5/5 8/8 3/3 10/13

20

Market Authorization hypothesis

2014 2015 2016 2017 2018

SIM

SOF/LDV

VIEKIRAX Exvira

SOF/VEL

Gra/Elb

ODV/AL335/SIM?

2DAA 3DAA

SOF

DCV

Gra/ MK-3682

/MK-8408

SOF/VEL/

GS-9857

ABT-493

/ABT-530

SOF/DCV Pan genotypic activity

Treatment of patients who failed previous DAAs regimen

All G3 G2 G4, 6 G1

63/63 127/128 9/9 34/35 21/21

1 relapse

ITT mITT

6 6

20 22

19 22

6 6

20 21

19 20

SOF/ VEL/ GS-9857

12 weeks

SVR 12

ABT-493 / ABT-530

12 weeks

in GT-1 patients

Lawitz E. et al EASL 2016, Abs. PS008

Poordad F. et al. EASL 2016, Abs. GS11

SOF/VEL/GS-9857 for 12 weeks in genotypes 1 to 6 patients with DAAs failure

100 % SVR 12

51/51

99 % SVR 12

76/77

40 % No RAS

(51/128)

60 % Baseline RAS (77/128)

20 %

NS5A RAS

only

15 % NS3 RAS

only

23 %

multiple RAS

2 % NS5B RAS only

Impact of baseline RAS on SVR 12

Lawitz E. et al. EASL 2016, Abs. PS008.

Relapse : prior treatment and RASs evolution

Lawitz E. et al, EASL 2016, Abs. PS008.

Peg-IFN 8 sem.

0

1

2

3

4

5

6

7

8

HC

V R

NA

(log

10 U

I/m

L)

SOF + RBV 32 weeks.

• 58 yo GT-3 women with cirrhosis, HCV RNA 7,0 log10 IU/ml

NS5A Y93H (> 99 %)*

NS3 No RAS

NS5B No RAS

NS5A Y93H (> 99 %)

NS3 Q80R (41 %)

NS5B No RAS

SOF/VEL + GS-9857 12 weels.

Follow up

S8

SOF/VEL/GS-9857 for 12 weeks in genotypes 1 to 6 patients with DAAs failure


• Monocenter phase 2 trial in GT1 patients with DAAs failure : G1a (88 %), cirrhosis (50 %)

• Two arms study : SOF/VEL/GS-9857 (second generation PI) 12 weeks vs SOF/VEL/GS-9857 + RBV 12 weeks.

Previous treatment (≥ 6 weeks) SVR 12

6 %

14 %

20 %

31 %

16 %

12 %

NS5A

NS3

NS5B

NS5A 41 %

(20/49) No NS5A

59 % (29/49)

SOF/VEL/GS-9857 12 weeks.

SOF/VEL/GS-9857 + RBV 12 weeks.

100 96

24/24 24/25

SOF/VEL/GS-9857 for 12 weeks : A good option in GT-1 DAAs failure

deep sequencing


Resistance profil in the relapser Impact of RAS on SVR

• 61 yo African American male with cirrhosis and IL28B CC

75 % baseline RAS (36/48)

97 % SVR 12

35/36

100 % SVR 12

12/12

15 % NS5A RAS

29 % NS3 RAS

31 % Multiples

RAS

25 % No RAS (12/48)

0

1

2

3

4

5

6

7

HC

V R

NA

(lo

g10

UI/

ml)

LDV/SOF

24 weeks. SOF/VEL/GS-9857 + RBV

12 weeks. FU-4

M28V (1,7 %) Q30H (3,2 %) L31M > 99 %)

M28T (> 99 %) Q30 L (2,4 %) Q30R (97,3 %) L31M (> 99 %)

V36M (> 99 %) Q41R (> 99 %)

D168G (96,4 %) D168S (2,4 %)

0 RAS

0 RAS

0 RAS

NS5A

NS3

NS5B

SOF/VEL/GS-9857 for 12 weeks : A good option in GT-1 DAAs failure

ITT Modified ITT

Dose ABT-493

ABT-530

Dose RBV

200 mg

120 mg

300 mg

120 mg

800 mg

300 mg

120 mg

200 mg

120 mg

300 mg

120 mg

800 mg

300 mg

120 mg

Breakthrough 0 0 1 0 0 1

Relapse 0 1 0 0 1 0

Lost of FU 0 1 2 - - -

SVR 12 = 100 % among patient with

baseline NS5A Y93 mutation

SVR = 100 % among patients with

baseline NS3 Q80 or R155 mutations

100 91 86

100 95 95

0

20

40

60

80

100

6 6

20 22

19 22

6 6

20 21

19 20

ABT-493 and ABT-530 in GT-1 non cirrhotic DAAs failure patients

Poordad F. et al. EASL 2016, Abs. GS11.

SVR 12 Impact of baseline RAS on SVR 12

NO RAS

(n = 6) NS3 RAS only

(n = 15)

NS5A RAS Only

(n = 10)

NS3 and NS5A RAS

(n = 16) SVR 12 15/16 (94 %)

SVR 12 9/10

(90 %)

SVR 12 15/15

(100 %)

SVR 12 6/6

(100 %)

Conclusions

• In case of DAAs failure consider resistance testing prior retreatment.

• The re-treatment regimen should contain

• Sofosbuvir because of the high barrier to resistance

• 1 or 2 other DAA(s), if possible with no cross-resistance with the DAA(s) already administered

• Ribavirin

• Treatment duration should be 12 or 24 weeks (recommended in F3-F4)

• For those with multiple RASs against NS3 and NS5A, and advance disease, retreatment must be cautious with available drug and future treatment may be more promising

Thank you for your attention

Failure after treatment with DAAs: What to...

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