Clinical case: re-treatment of HCV DAA failure with 3-class resistance

Pavel Khaykin, MainFachArzt, Frankfurt M., Germany

Considerations for DAA Regimen Failure

Previous TherapyDAA classes

RBVDuration

ResistanceOthers

AdherenceDrug interactions

PatientCirrhosis

BMIRenal disease

Most commonly identified factors in DAA-treatment failures

Buti M et al J Hepatol 2015; 63: 1511-1522

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b Patient

32-yr-old Caucasian man with HCV, treatment naïve, Non HIV/HBV

Origin : Ukraine

HCV Risk: unknown

Physical exam: BMI 24, no ascites, no edema, no clinical symptoms

Non Cirrhotic confirmed by elastography (8.9 kPa)

Ultrasound: no other findings

HCV PCR: 1.700.000 IU/ml

Genotyp 1 b

No co-medication

Current Laboratory

ParameterResult

Platelets/mm3 150,000

Albumin, g/dL 3.7

ALT, IU/L 47

AST, IU/L 56

Total bilirubin, mg/dL 0.9

INR 1.2

Baseline Resistance (RASs):

NS3- Non

NS5A –L31M

NS5B- Non

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b Patient

December 2015 DAA first Treatment with

Paritaprevir/Ombitasvir/ritonavir + Dasabuvir for 12 weeks

PEARL-II & -III: about 100 % SVR at GT1b

476 GT1b-Patients

PEARL-III GT1bNaive

PEARL-II GT1bExp

Impact of Baseline RAVs on Efficacy of OBV/PTV/RTV + DSV ± RBV in 1

Analysis of data from 5 phase III trials using NGS; all pts treated with OBV/PTV/RTV + DSV ± RBV on label (based on subgenotype, previous treatment, and cirrhosis)

▪ SVR12 rate 100% in pts with GT1b HCV, regardless of BL RAVs

Sarrazin C, et al. EASL 2016. Abstract LBP503

GT1a (1% NGS detection limit))

DSV Specific

100

80

60

40

20

0

100 97 9797

Q80K

11/11

140/145

262/269

391/403

SV

R12 (

%)

PTV Specific

94 9498 98

NS NS

89/95

113/120

295/300

319/325

OBV Specific NS5A Class

96 97

NS

24/25

371/382

With RAVs

Resistance-Associated Variant Type

Without RAVs

n/N

=

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b Patient

December 2015 DAA first Treatment with

Paritaprevir/Ombitasvir/ritonavir + Dasabuvir for 12 weeks

HCV PCR W4: negative

HCV PCR W8: negative

HCV PCR W12 (EOT): 720.000 IU/ml Breakthrough???

Genotyp Re-confirm: 1 b

Compliance: 100 %

No Co-medication

No Risk for Re-Infection

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b PatientResistance

Baseline Resistance (RASs):

NS3- Non

NS5A –L31M

NS5B- Non

After Failure Resistance (RASs):

NS3- Y56H, D168V

NS5A – L31M, Y93H (New)

NS5B- Non-Nuk: C316N, S556G

NS5B- Nuk: L159F, C316N

9

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b PatientResistance

After Failure Resistance (RASs):

NS3- Y56H, D168V (Paritaprevir)

NS5A – L31M, Y93H (Ombitasvir)

NS5B- Non-Nuk: C316N, S556G (Dasabuvir)

NS5B- Nuk: L159F, C316N

11

Fold

Change

Genotype 1a Genotype 1b

M28T Q30R L31M/V Y93H/N L31V Y93H/N

Ledipasvir 20x > 100x> 100x/

> 100x

> 1000x/

> 10,000x> 100x/--

Ombitasvir > 1000x > 100x< 3x > 10,000x/

> 10,000x< 10x 20x/50x

> 100x

Daclatasvir > 100x > 1000x> 100x/

> 1000x

> 1000x/

> 10,000x< 10x 20x/50x

Elbasvir 20x > 100x> 10x > 1000x/

> 1000x< 10x > 100x/--

> 100x

Velpatasvir < 10x < 3x 20x/50x> 100x/

> 1000x< 3x < 3x/--

Pibrentasvir < 3x < 3x < 3x < 10x/< 10x < 3x < 3x/< 3x

Ruzasvir < 10x < 10x < 10x < 10x < 10x < 10x

Broad Cross-Resistance With “Early-Generation” NS5A Inhibitors

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b PatientResistance

After Failure Resistance (RASs):

NS3- Y56H, D168V (Paritaprevir)

NS5A – L31M, Y93H (Ombitasvir)

NS5B- Non-Nuk: C316N, S556G (Dasabuvir)

NS5B- Nuk: L159F, C316N

Resistance Characteristics of HCV Antiviral Classes

*Anticipated FDA approvals.

ClassAntiviral

PotencyGT Activity Resistance Barrier FDA Approvals

NS3 protease inhibitor[1] +++ to ++++1, 4

(± 2, 3, 6)

Low

to

high

Simeprevir (2013)

Paritaprevir (2014)

Grazoprevir (2016)

Voxilaprevir (2017*)

Glecaprevir (2017*)

NS5B nucleotide[2] ++++ 1-6 Very highSofosbuvir (2013)

Uprifosbuvir (2018?*)

NS5B nonnucleoside[2] ++ 1 Low Dasabuvir (2014)

NS5A inhibitor[3] ++++1, 4, 6

(± 2, 3)

Low

to

high

Ledipasvir (2014)

Daclatasvir (2015)

Ombitasvir (2014)

Elbasvir (2016)

Velpatasvir (2016)

Pibrentasvir (2017*)

Ruzasvir (2018?*)

Genotypic resistance testing

Consider waiting

GT1DAA failure

NS5A RASs

SOF-based triple or quad regimens

16/24 wk failure?

YESNO

NS3 (R155, A156, D168) + NS5A RASs

LDV/SOF + RBV (24)SOF/VEL + RBV (24) For 2-drug regimens:

1. Increase duration

2. Add RBV

SMV + SOF + RBV (24)SOF/VEL + RBV (24)

(esp if no L31M, Y93H)SOF quad/triple

SOF/VEL + RBV (24)(esp if no L31M, Y93H)

SOF quad/triple

New therapies GLE/PIB

SOF/VEL/VOX

Or

wait for

GLE/PIB or

SOF/VEL/VOX

No NS5A RASs

QUARTZ-I: OBV/PTV/RTV + DSV + SOF ± RBV for 3D Regimen DAA-Experienced Pts With GT1 HCV

Multicenter, open-label phase II study

14/20 GT1a had previous OBV/PTV/RTV + DSV failure; no previous LDV/SOF failure

BL RASs: D168E/V (n = 5);

Y93C/F/H (4);

Q30E/H/R (n = 12)

Poordad F, et al. EASL 2016. Abstract SAT-156.

Noncirrhotic

GT1a

OBV/PTV/RTV + DSV

+ SOF

(n = 2)

OBV/PTV/RTV + DSV

+ SOF + RBV

(n = 14)

OBV/PTV/RTV + DSV + SOF + RBV

(n = 6)

Cirrhotic

GT1a

GT1b

±cirrhosis

Wk 24Wk 12

GT1b

±cirrhosis

GT1a

No Cirrhosis

GT1a

Cirrhosis

All

Clinical case: Non-cirrhotic, naive, non-HIV/HBV, Gen 1b PatientRe-treatment

April 2015 DAA Re-treatment

Sofosbuvir+Daclatasvir+Simeprevir+Ribavirin for 12 Weeks (SOF Quad)

HCV PCR W4: negative

HCV PCR W8: negative

HCV PCR W12 (EOT): negative

HCV PCR SVR 4: negative

HCV PCR SVR 12: negative

HCV PCR SVR 24: negative

HCV PCR SVR 48: negative

SV

R12,

%

Overall*No

Cirrhosis Cirrhosis

SVR12 Results Overall and by Cirrhosis Status

POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1–6

Bourliere M, et al. N Engl J Med 2017;376:2134-46

253/263

6 relapses1 breakthrough**2 withdrew consent1 LTFU

* p <0.001 for superiority compared with prespecified 85%

performance goal for SOF/VEL/VOX

** Exposure was consistent with non-adherence

140/142 113/121

1 withdrew consent1 LTFU

6 relapses1 breakthrough**1 withdrew consent

Two patients had S282T at baseline, both achieved SVR12

SVR12 by Baseline RAS (15% cutoff)

Bourliere M, et al. N Engl J Med 2017;376:2134-46

SOF/VEL/VOX 12 weeks83% Baseline RASs

(205/248)*

NoRASs

NS5A Only

98% SVR12

42/43

97% SVR12

199/205

20

40

60

80

100

SV

R12 (

%)

NS3+NS5A

Any RAS

NS3 Only

NS5A=97% SVR

NS3=100% SVR

NS3+NS5A=97% SVR

POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1–6

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Thank you for yourattention!