HCV Alerts- Rapid Response to Practice-Changing Advances From EASL 2015

HCV Alerts: Rapid Response to Practice-Changing Advances

Supported by an educational grant from AbbVie.

Practice-Changing Advances From EASL 2015

clinicaloptions.com/hepatitisHCV Alerts: Rapid Response to Practice-Changing Advances

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Faculty

Mark S. Sulkowski, MDProfessor of MedicineMedical Director, Viral Hepatitis CenterDivisions of Infectious Diseases and Gastroenterology/HepatologyJohns Hopkins University School of MedicineBaltimore, Maryland

Program Director:

Paul Y. Kwo, MDProfessor of MedicineMedical Director of TransplantationDivision of Medicine/ Gastroenterology/Hepatology Indiana University School of MedicineIndianapolis, Indiana


Faculty Disclosures

Mark S. Sulkowski, MD, has disclosed that he has received consulting fees from AbbVie, Achillion, Bristol‐Myers Squibb, Gilead Sciences, Janssen, and Merck; funds for research support from AbbVie, Bristol‐Myers Squibb, Gilead Sciences, and Merck; and data and safety monitoring board funding (to his institution) from Gilead Sciences.

Paul Y. Kwo, MD, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Conatus, Gilead Sciences, Janssen, Merck, and Roche and consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.

Managing HCV Infectionin Renal Disease


RUBY-1: OMV/PTV/RTV + DSV ± RBV in Tx-Naive, Noncirrhotic GT1 Pts With CKD Interim analysis of multicenter, open-label phase IIIb study

Ombitasvir/paritaprevir/ritonavir 25/150/100 mg QD + dasabuvir 250 mg BID ± ribavirin* 200 mg QD for 12 wks

Key baseline characteristics

– F2 fibrosis: 30%; F3 fibrosis: 20%

– CKD stage 4 (eGFR 15-30): 35%; CKD stage 5 (eGFR < 15): 65%

– 65% of pts on hemodialysis

Pockros PJ, et al. EASL 2015. Abstract L01.

*RBV dosed 4 hrs before hemodialysis in hemodialysis pts; weekly hemoglobin assessment in Month 1 and then Wks 6, 8, 12; RBV suspended in pts with > 2 g/dL decline in hemoglobin in < 4 wks or hemoglobin < 10 g/dL; RBV dosing resumed at clinician’s discretion if hemoglobin normalized.


RUBY-1: Safety and Interim Efficacy

OMV/PTV/RTV + DSV ± RBV well tolerated for GT1 HCV and advanced CKD

No treatment-related serious AEs, discontinuations, or significant changes in liver or renal function to date

RBV dose interruption in 8/13 GT1a pts (6 in first 4 wks)

– 4 pts received EPO, 1 pt with hemoglobin < 8 mg/dL

Most AEs mild to moderate

Interim virologic efficacy

– SVR4 in 10/10 pts reaching posttreatment Wk 4

– SVR12 in 2/2 pts reaching posttreatment Wk 12

– No virologic failures observed as of time of reporting

Pockros PJ, et al. EASL 2015. Abstract L01.

AEs Found in > 3 Pts, n

GT1b:OMV/PTV/RTV

+ DSV(n = 7)

GT1a:OMV/PTV/RTV + DSV + RBV

(n = 13)

Anemia 0 8

Fatigue 2 4

Diarrhea 1 4

Nausea 0 5


Saxena V, et al. EASL 2015. Abstract LP08.

HCV TARGET: Similar SVR12 Rates With SOF Regimens Regardless of eGFR Longitudinal observational study in 1893 sequentially enrolled pts

– Sofosbuvir + simeprevir the most common regimen used Overall SVR12 rates high and similar (> 80%) across renal function

strata in pts with known treatment outcome

81

48

88

17

≤ 30*

100

80

60

40

20

0

SV

R12

(%

)

eGFR

81

1393

89

140

31-45 46-60 > 60

N =

*Sofosbuvir use with eGFR < 30 mL/min/1.73m2 is off label.


HCV TARGET: Rates of Anemia/Renal AEs Inversely Related to Baseline eGFR Outcome in Pts Completing SOF-Containing Therapy ± RBV, % (n)

eGFR ≤ 30(n = 17)

eGFR 31-45(n = 56)

eGFR 46-60(n = 157)

eGFR > 60(n = 1559)

Anemia AEs 35 (6) 29 (16) 24 (37) 16 (246)

Transfusions 12 (2) 9 (5) 2 (3) 2 (31)

Erythropoietin 6 (1) 14 (8) 9 (14) 3 (50)

RBV dose reduction* 38 (3) 30 (8) 42 (33) 19 (185)

RBV discontinuation* 0 15 (4) 1 (1) 1 (12)

Worsening renal function 29 (5) 11 (6) 3 (4) 1 (14)

Renal or urinary AEs 29 (5) 11 (6) 8 (13) 5 (84)

Serious AEs 18 (3) 23 (13) 5 (8) 6 (100)

Cardiac AEs 6 (1) 4 (2) 5 (8) 3 (53)

Saxena V, et al. EASL 2015. Abstract LP08.

*Among pts who received RBV


Take-Home Points: HCV Therapy in the Setting of Renal Insufficiency Safety and efficacy data now available for OMV/PTV/RTV

+ DSV ± RBV in hemodialysis pts

– In pts with genotype 1a HCV, AEs remain a concern with RBV, even at low doses

Efficacy data now for available for SOF-based regimens in pts with eGFR ≤ 30

– Owing to decreased excretion of metabolite GS-331007, safety remains uncertain

Role of Resistance Testing in HCV Retreatment


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

R12

(%

)

All No Yes

71 6874

15/22

14/19

No Yes8 Wks 12 Wks

Cirrhosis Previous Tx Duration

BL NS5A RAVs

80

4660

100

24/30

5/11

11/11

18/30n/N =

29/41


OPTIMIST-2: SMV + SOF for 12 Wks in Cirrhotic Tx-Naive and Tx-Exp’d GT1 Pts Multicenter, open-label, single-arm

phase III trial[1]

Key baseline characteristics

– 70% GT1a (47% with Q80K)

– 72% IL28B non-CC

– 18% black, 16% Hispanic

– 51% treatment exp’d

– 18% with platelets < 90,000 cells/mm3

– 51% with albumin < 4 g/dL

Among cirrhotic pts, SVR12 rates were lower in those with GT1a with Q80K mutation

OPTIMIST-1: No impact of Q80K seen in noncirrhotic pts with GT1a[2]

1. Lawitz E, et al. EASL 2015. Abstract LP04. 2. Kwo P, et al. EASL 2015. Abstract LB14.

100

80

60

40

20

0

SV

R12

(%

)

GT1a GT1a WithQ80K

GT1a WithoutQ80K

GT1b

60/72 25/34 35/38 26/31

8374

9284

n/N =


Take-Home Points: 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

Advances in the Treatment of Genotype 3 HCV Infection


Treatment Naive Treatment Experienced

BOSON: SVR12 in GT3 by Tx History and Cirrhosis Status

Foster GR, et al. EASL 2015. Abstract LO5.

58/70

65/72

68/71

12/21

18/22

21/23

26/34

17/36

30/35

44/54

49/52

41/54

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

8390

96

57

8291

7682

94

47

7786100

80

60

40

20

0

SV

R12

(%

)

SOF + RBV for 16 wks SOF + RBV for 24 wks SOF + pegIFN/RBV for 12 wks

n/N =

Multicenter, randomized, open-label study


BOSON: SOF + RBV + PegIFN for 12 Wks Was Safe and Well Tolerated

Foster GR, et al. EASL 2015. Abstract LO5.

Safety Outcome, % (n)16 Wks of

SOF + RBV(n = 196)

24 Wks of SOF + RBV

(n = 199)

12 Wks of SOF + PegIFN/RBV

(n = 197)

AEs 94 (185) 95 (188) 99 (195)

Grade 3/4 AEs 6 (11) 4 (7) 8 (15)

Serious AEs 4 (8) 5 (10) 6 (12)

Treatment discontinuation for AEs 2 (3) 1 (2) <1 (1)

Laboratory abnormalities

Grade 3/4 15 (30) 15 (29) 38 (74)

Hemoglobin < 10 g/dL 4 (7) 6 (12) 12 (24)

Hemoglobin < 8.5 g/dL 0 0 1 (2)

Platelets < 50,000 cells/mm3 <1 (1) 0 5 (9)

Low rates of serious AEs, laboratory abnormalities, and treatment discontinuations due to AEs


Take-Home Points: Treatment for Genotype 3 HCV Infection SOF + pegIFN/RBV for 12 wks may be best current option

in treatment-experienced pts with GT3 HCV infection

– Addition of pegIFN to SOF + RBV for 12 wks associated with highest rate of SVR12 in treatment-experienced pts with GT3, particularly those with cirrhosis

To achieve high SVR rates with SOF in GT3, an additional active drug may be needed

– Studies of combinations of novel DAAs with increased activity against GT3 are under way

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HCV Alerts- Rapid Response to Practice-Changing Advances From EASL 2015